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OutlineChapter 14- Hypovolemic States- Etiology - True volume depletion occurs when fluid is lost from from the extracellular fluid at a rate exceeding intake - Can come the GI tract - Lungs - Urine - Sequestration in the body in a “third space” that is not in equilibrium with the extracellular fluid. - When losses occur two responses ameliorate them - Our intake of Na and fluid is way above basal needs - This is not the case with anorexia or vomiting - The kidney responds by minimizing further urinary losses - This adaptive response is why diuretics do not cause progressive volume depletion - Initial volume loss stimulates RAAS, and possibly other compensatory mechanisms, resulting increased proximal and collecting tubule Na reabsorption. - This balances the diuretic effect resulting in a new steady state in 1-2weeks - New steady state means Na in = Na out - GI Losses - Stomach, pancreas, GB, and intestines secretes 3-6 liters a day. - Almost all is reabsorbed with only loss of 100-200 ml in stool a day - Volume depletion can result from surgical drainage or failure of reabsorption - Acid base disturbances with GI losses - Stomach losses cause metabolic alkalosis - Intestinal, pancreatic and biliary secretions are alkalotic so losing them causes metabolic acidosis - Fistulas, laxative abuse, diarrhea, ostomies, tube drainage - High content of potassium so associated with hypokalemia - [This is a mistake for stomach losses] - Bleeding from the GI tract can also cause volume depletion - No electrolyte disorders from this unless lactic acidosis - Renal losses - 130-180 liters filtered every day - 98-99% reabsorbed - Urine output of 1-2 liters - A small 1-2% decrease in reabsorption can lead to 2-4 liter increase in Na and Water excretion - 4 liters of urine output is the goal of therapeutic diuresis which means a reduction of fluid reabsorption of only 2% - Diuretics - Osmotic diuretics - Severe hyperglycemia can contribute to a fluid deficit of 8-10 Iiters - CKD with GFR < 25 are poor Na conservers - Obligate sodium losses of 10 to 40 mEq/day - Normal people can reduce obligate Na losses down to 5 mEq/day - Usually not a problem because most people eat way more than 10-40 mEq of Na a day. - Salt wasting nephropathies - Water losses of 2 liters a day - 100 mEq of Na a day - Tubular and interstitial diseases - Medullary cystic kidney - Mechanism - Increased urea can be an osmotic diuretic - Damage to tubular epithelium can make it aldo resistant - Inability to shut off natriuretic hormone (ANP?) - The decreased nephro number means they need to be able to decrease sodium reabsorption per nephron. This may not be able to be shut down acutely. - Experiment, salt wasters can stay in balance if sodium intake is slowly decreased. (Think weeks) - Talks about post obstruction diuresis - Says it is usually appropriate rather than inappropriate physiology. - Usually catch up solute and water clearance after releasing obstruction - Recommends 50-75/hr of half normal saline - Talks briefly about DI - Skin and respiratory losses - 700-1000 ml of water lost daily by evaporation, insensible losses (not sweat) - Can rise to 1-2 liters per hour in dry hot climate - 30-50 mEq/L Na - Thirst is primary compensation for this - Sweat sodium losses can result in hypovolemia - Burns and exudative skin losses changes the nature of fluid losses resulting in fluid losses more similar to plasma with a variable amount of protein - Bronchorrhea - Sequestration into a third space - Volume Deficiency produced by the loss of interstitial and intravascular fluid into a third space that is not in equilibrium with the extracellular fluid. - Hip fracture 1500-2000 into tissues adjacent to fxr - Intestinal obstruction, severe pancreatitis, crush injury, bleeding, peritonitis, obstruction of a major venous system - Difference between 3rd space and cirrhosis ascities - Rate of accumulation, if the rate is slow enough there is time for renal sodium and water compensation to maintain balance. - So cirrhotics get edema from salt retension and do not act as hypovolemia - Hemodynamic response to volume depletion - Initial volume deficit reduced venous return to heart - Detected by cardiopulmonary receptors in atria and pulmonary veins leading to sympathetic vasoconstriction in skin and skeletal muscle. - More marked depletion will result in decreased cardiac output and decrease in BP - This drop in BP is now detected by carotid and aortic arch baroreceptors resulting in splanchnic and renal circulation vasoconstriction - This maintains cardiac and cerebral circulation - Returns BP toward normal - Increase in BP due to increased venous return - Increased cardiac contractility and heart rate - Increased vascular resistance - Sympathetic tone - Renin leading to Ang2 - These can compensate for 500 ml of blood loss (10%) - Unless there is autonomic dysfunction - With 16-25% loss this will not compensate for BP when patient upright - Postural dizziness - Symptoms - Three sets of symptoms can occur in hypovolemic patients - Those related to the manner in which the fluid loss occurs - Vomiting - Diarrhea - Polyuria - Those due to volume depletion - Those due to the electrode and acid base disorders that can accompany volume depletion - The symptoms of volume depletion are primarily related to the decrease in tissue perfusion - Early symptoms - Lassitude - Fatiguability - Thirst - Muscle cramps - Postural dizziness - As it gets more severe - Abdominal pain - Chest pain - Lethargy - Confusion - Symptomatic hypovolemia is most common with isosmotic Na and water depletion - In contrast pure water loss, causes hypernatremia, which results in movement of water from the intracellular compartment to the extracellular compartment, so that 2/3s of volume loss comes from the intracellular compartment, which minimizes the decrease in perfusion - Electrolyte disorders and symptoms - Muscle weakness from hypokalemia - Polyuria/poly dips is from hyperglycemia and hypokalemia - Lethargy, confusion, Seizures, coma from hyponatremia, hypernatremia, hyperglycemia - Extreme salt craving is unique to adrenal insufficiency - Eating salt off hands ref 18 - Evaluation of the hypovolemic patient - Know that if the losses are insensible then the sodium should rise - Volume depletion refers to extracellular volume depletion of any cause, while dehydration refers to the presence of hypernatremia due to pure water loss. Such patients are also hypovolemic. - Physical exam is insensitive and nonspecific - Finding most sensitive and specific finding for bleeding is postural changes in blood pressure - I don't find this very specific at all! - Recommends laboratory confirmation regardless of physical exam - Skin and mucous membranes - Should return too shape quickly - Elastic property is called Turgur - Not reliable is patients older than 55 to 60 - Dry axilla - Dry mucus membranes - Dark skin in Addison's disease Frim increased ACTH - Arterial BP - As volume goes down so does arterial BP - Marked fluid loss leads to quiet korotkoff signs - Interpret BP in terms of the patients “normal BP” - Venous pressure - Best done by looking at the JVP - Right atrial and left atrial pressure - LV EDP is RAP + 5 mmHg - Be careful if valvular disease, right heart failure, cor pulmonare, - Figure 14-2 - Shock - 30% blood loss - Lab Data - Urine Na concentration - Should be less than 25 mmol/L, can go as low as 1 mmol/L - Metabolic alkalosis can throw this off - Look to the urine chloride - Figure 14-3 - Renal artery stenosis can throw this off - FENa - Mentions that it doesn't work so well at high GFR - Urine osmolality - Indicates ADH - Volume depletion often associated with urine osm > 450 - Impaired by - Renal disease - Osmotic diuretic - Diuretics - DI - Mentions that severe volume depletion and hypokalemia impairs urea retension in renal medulla - Points out that isotonic urine does not rule out hypovolemia - Mentions specific gravity - BUN and Cr concentration - Normal ratio is 10:1 - Volume depletion this goes to 20:1 - Serum Na - Talks about diarrhea - Difference between secretory diarrhea which is isotonic and just causes hypovolemia - And osmotic which results in a lower electrolyte content and development of hypernatremia - Talks about hyperglycemia - Also can cause the sodium to rise from the low electrolyte content of the urine - But the pseudohyponatraemia can protect against this - Plasma potassium - Treatment - Both oral and IV treatment can be used for volume replacement - The goal of therapy are to restore normovolemia - And to correct associated acid-base and electrolyte disorders - Oral Therapy - Usually can be accomplished with increased water and dietary sodium - May use salt tablets - Glucose often added to resuscitation fluids - Provides calories - Promotes intestinal Na reabsorption since there is coupled Na and Glucose similar to that seen in the proximal tubule - Rice based solutions provide more calories and amino acids which also promote sodium reabsorption - 80g/L of glucose with rice vs 20 g/L with glucose alone - IV therapy - Dextrose solutions - Physiologically equivalent to water - For correcting hypernatremia - For covering insensible losses - Watch for hyperglycemia - Footnote warns against giving sterile water - Saline solutions - Most hypovolemic patients have a water and a sodium deficit - Isotonic saline has a Na concentration of 154, similar to that of plasma see page 000 - Half-isotonic saline is equivalent to 550 ml of isotonic saline and 500 of free water. Is that a typo? - 3% is a liter of hypertonic saline and 359 extra mEq of Na - Dextrose in saline solutions - Give a small amount of calories, otherwise useless - Alkalinizing solutions - 7.5% NaHCO3 in 50 ml ampules 44 mEq of Na and 44 mEq of HCO3 - Treat metabolic acidosis or hyperkalemia - Why 44 mEq and not 50? - Do not give with calcium will form insoluble CaCO3 - Polyionic solutions - Ringers contains physiologic K and Ca - Lactated Ringers adds 28 mEq of lactate - Spreads myth of LR in lactic acidosis - Potassium chloride - Available as 2 mEq/mL - Do not give as a bolus as it can cause fatal hyperkalemia - Plasma volume expanders - Albumin, polygelastins, hetastarch are restricted to vascular space - 25% albumin can pull fluid into the vascular space - 25% albumin is an albumin concentration of 25 g/dL compare to physiologic 4 g/dL - Says it pulls in several times its own volume - 5% albumin is like giving plasma - Blood - Which fluid? - Look at osmolality, give hypotonic fluids to people with high osmolality - Must include all electrolytes - Example of adding 77 mEw of K to 0.45 NS and making it isotonic - DI can be replaced with dextrose solutions, pure water deficit - Case 14-3 - Diarrhea with metabolic acidosis - He chooses 0.25 NS with 44 mEq of NaCl and 44 NaHCO3 - Talks about blood and trauma - Some studies advocate delaying saline until penetrating trauma is corrected APR about to. Keep BP low to prevent bleeding. Worry about diluting coagulation factors - Only do this if the OR is quickly available - Volume deficit - Provides formula for water deficit and sodium deficit - Do not work for isotonic losses - Provides a table to adjust fluid loss based on changes in Hgb or HCTZ - Says difficult to estimate it from lab findings and calculations - Follow serial exams - Serial urine Na - Rate of replacement - Goal is not to give fluid but to induce a positive balance - Suggests 50-100 ml/hr over what is coming out of the body - Urine - Insensibles 30-50 - Diarrhea - Tubes - Hypovolemic shock - Due to bleeding - Sequesting in third space - Why shock? - Progressive volume depletion leads to - Increased sympathetic NS - Increased Ang 2 - Initially this maintains BP, cerebral and coronary circulation - But this can decrease splanchnic, renal and mucocutaneous perfusion - This leads to lactic acicosis - This can result in intracellular contents moving into circulation or translocation of gut bacteria - Early therapy to prevent irreversible shock - In dogs need to treat with in 2 hours - In humans may need more than 4 hours - Irreversible shock associated with pooling of blood in capillaries - Vasomotor paralysis - Hyperpolarization of vascular smooth muscle as depletion of ATP allows K to flowing out from K channels opening. Ca flows out too leading to vasodilation - Glyburide is an K-ATP channel inhibitor (?) caused increased vasoconstriction and BP - Pluggin of capillaries by neutrophils - Cerebral ischemia - Increased NO generation - Which Fluids? - Think of what is lost and replace that. - Bleeding think blood - Raise the hct but not above 35 - Acellular blood substitutes, looked bad at the time of this writing - Di aspirin cross linked hemoglobin had increased 2 and 28 day mortality vs saline - Colloids sound great but they fail in RCTs - SAFE - FEAST - Points out that saline replaces the interstitial losses why do we think those losses are unimportant - Pulmonary circulation issue - Pulmonary circulation is more leaky so oncotic pressure less effective there - Talks about the lungs be naturally protected from pulmonary edema - Rate of fluid - 1-2 liters in first hour - Suggests CVP or capillary wedge pressure during resuscitation - No refs in the rate of fluid administration section - Lactic acidosis - Points out that HCO can impair lactate utilization - Also states that arterial pH does not point out what is happening at the tissue level. Suggests mixed-venous sample.ReferencesJCI - Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia and a nice review of this topic: Altered Prostaglandin Signaling as a Cause of Thiazide-Induced HyponatremiaThe electrolyte concentration of human gastric secretion. https://physoc.onlinelibrary.wiley.com/doi/10.1113/expphysiol.1960.sp001428A classic by Danovitch and Bricker: Reversibility of the “Salt-Losing” Tendency of Chronic Renal Failure | NEJMOsmotic Diuresis Due to Retained Urea after Release of Obstructive Uropathy | NEJMIs This Patient Hypovolemic? | Cardiology | JAMAAnd by the same author, a textbook: Steven McGee. 5th edition. Evidence-Based Physical Diagnosis Elsevier Philadelphia 2022. ISBN-13: 978-0323754835The clinical course and pathophysiological investigation of adolescent gestational diabetes insipidus: a case report | BMC Endocrine DisordersSensitivity and specificity of clinical signs for assessment of dehydration in endurance athletes | British Journal of Sports MedicineDiagnostic performance of serum blood urea nitrogen to creatinine ratio for distinguishing prerenal from intrinsic acute kidney injury in the emergency department | BMC NephrologyThe meaning of the blood urea nitrogen/creatinine ratio in acute kidney injury - PMCLanguage guiding therapy: the case for dehydration vs volume depletion https://www.acpjournals.org/doi/10.7326/0003-4819-127-9-199711010-00020?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmedValidation of a noninvasive monitor to continuously trend individual responses to hypovolemiaReferences for Anna's voice of God on Third Spacing : Shires Paper from 1964 (The ‘third space' – fact or fiction? )References for melanie's VOG:1. Appraising the Preclinical Evidence of the Role of the Renin-Angiotensin-Aldosterone System in Antenatal Programming of Maternal and Offspring Cardiovascular Health Across the Life Course: Moving the Field Forward: A Scientific Statement From the American Heart Association2. excellent review of RAAS in pregnancy: The enigma of continual plasma volume expansion in pregnancy: critical role of the renin-angiotensin-aldosterone systemhttps://journals-physiology-org.ezp-prod1.hul.harvard.edu/doi/full/10.1152/ajprenal.00129.20163. 10.1172/JCI107462- classic study in JCI of AngII responsiveness during pregnancy4. William's Obstetrics 26th edition!5. Feto-maternal osmotic balance at term. A prospective observational study

ReferencesJC mentioned that the diagnostic accuracy of 24 hour urine collection increases with more collections! Metabolic evaluation of patients with recurrent idiopathic calcium nephrolithiasisWe didn't refer to a particular study on sodium intake and the 24 hour urine but this meta-analysis Comparison of 24‐hour urine and 24‐hour diet recall for estimating dietary sodium intake in populations: A systematic review and meta‐analysis - PMC 24‐hour diet recall underestimated population mean sodium intake.Anna looking up ace i and urinary sodium Effects of ACE inhibition on proximal tubule sodium transport | American Journal of Physiology-Renal PhysiologyThe original FENa paper by Espinel: The FeNa Test: Use in the Differential Diagnosis of Acute Renal Failure | JAMA | JAMA NetworkSchreir's replication and expansion of Espinel's data: Urinary diagnostic indices in acute renal failure: a prospective studyHere's a report from our own JC on the Diagnostic Utility of Serial Microscopic Examination of the Urinary Sediment in Acute Kidney Injury | American Society of NephrologyJC shared his journey regarding FENa and refers to his recent paper Concomitant Identification of Muddy Brown Granular Casts and Low Fractional Excretion of Urinary Sodium in AKIAnd Melanie's accompanying editorial Mind the Cast: FENa versus Microscopy in AKI : Kidney360 (with a great image from Samir Parikh)JC referenced this study from Schrier on FENa with a larger series: Urinary diagnostic indices in acute renal failure: a prospective study​​Nonoliguric Acute Renal Failure Associated with a Low Fractional Excretion of Sodium | Annals of Internal MedicineUrine sodium concentration to predict fluid responsiveness in oliguric ICU patients: a prospective multicenter observational study | Critical Care | Full TextA classic favorite: Acute renal success. The unexpected logic of oliguria in acute renal failure Marathon runners had granular casts in their urine without renal failure. Kidney Injury and Repair Biomarkers in Marathon RunnersCute piece from Rick Sterns on urine electrolytes! Managing electrolyte disorders: order a basic urine metabolic panelThe Urine Anion Gap: Common Misconceptions | American Society of NephrologyThe urine anion gap in context CJASNExcellent review from Halperin on urine chemistries (including some consideration of the TTKG): Use of Urine Electrolytes and Urine Osmolality in the Clinical Diagnosis of Fluid, Electrolytes, and Acid-Base Disorders - Kidney International ReportsRenal tubular acidosis (RTA): Recognize The Ammonium defect and pHorget the urine pH | SpringerLinkOutlineChapter 13- New part: Part 3, Physiologic approach to acid-base and electrolyte disorders - Do you remember the previous two parts? - Renal physiology - Regulation of water and electrolyte balance- Chapter 13: Meaning and application of urine chemistries - Measurement of urinary electrolyte concentrations, osmolality and pH helps diagnose some conditions - There are no fixed normal values - Kidney varies rate of excretion to match intake and endogenous production - Example: urine Na of 125/day can be normal if patient euvolemic on a normal diet, and wildly inappropriate in a patient who is volume depleted. - Urine chemistries are: - Useful - Simple - Widely available - Usually a random sample is adequate - 24-hour samples give additional context - Gives example of urinary potassium, with extra renal loss of K, urine K should be < 25, but if the patient has concurrent volume deficiency and urine output is only 500 mL, then urine K concentration can appropriately be as high as 40 mEq/L - Table 13-1 - Seems incomplete, see my notes on page 406 - What is Gravity ARF?- Sodium Excretion - Kidney varies Na to maintain effective circulating volume (I'd say volume homeostasis) - Urine Na affected by RAAS and ANP - Na concentration can be used to determine volume status - Urine Na < 20 is hypovolemia - Says it is especially helpful in determining the etiology of hyponatremia - Calls out SIADH and volume depletion - Used 40 mEq/L for SIADH - Also useful in AKI - Where differential is pre-renal vs ATN - In addition to urine Na (and FENa) look at urine osmolality - Again uses 40 mEq/l - Mentions FENa and urine osmolality - Urine Na can estimate dietary sodium intake - Suggests doing this during treatment of hypertension to assure dietary compliance - 24 hour urine Na is accurate with diuretics as long as the dose is stable and the drugs are chronic - Diuretics increase Na resorption in other segments of the tubule that are not affected by the diuretic - Points to increased AT2 induced proximal Na resorption and aldosterone induced DCT resoprtion - In HTN shoot for less than 100 mEq/Day - Urine Na useful in stones - Urine uric acid and urine Ca can cause stones and their handling is dependent on sodium - Low sodium diet can mask elevated excretion of these stone forming metabolites - 24-hour Na > 75 and should be enough sodium to avoid this pitfall - Pitfalls - Low urine sodium in bilateral renal artery stenosis or acute GN - High urine sodium with diuretics, aldo deficiency, advanced CKD - Altered water handling can also disrupt this - DI with 10 liters of urine and urine sodium excretion of 100 mEq is 10 mEq/L but in this case there is no volume deficiency - Opposite also important, a lot of water resorption can mask volume deficiency by jacking up the urine sodium - Advises you to use the FENa - THE FENA - < 1% dry - >2-3% ATN - It will fail with chronic effective volume depletion - Heart failure, cirrhosis, and burns - Suggests that tubular function will be preserved in those situations - Also with contrast, rhabdo, pigment nephropathy - Limitations - Dependent on the amount of Na filtered - Goes through the math of a normal person with GFR of 125/min and Na of 150 has filtered sodium of 27,000/day so if they eat 125-250 mEq their FENa will be 600-800 - Urine osm < plasma osm in face of hypernatremia indicates renal water loss due to lack of or resistance to ADH - In ATN urine OSM < 400 - In pre-renal disease it could be over 500 - Specific but not sensitive due to people with CKD who are unable to concentrate urine- Specific gravity - Plasma is 8-10% igher than plasma so specific gravity is 1.008 to 1.010 - Every 30-35 mOsm/L raises urine Osm of 0.001 - so 1.010 is 300-350 mOsm/L H2O - Glucose raises urine specific gravity more than osmolality - Same with contrast - Carbenicillin- pH - Normally varies with systemic acid-base status - PH should fall before 5.3 (usually below 5.0) with systemic metabolic acidosis - Above 5.3 in adults and 5.6 in children indicate RTA - PH goal 6.0-6.5 - Separate individual RTAs through FR of HCO3 at various serum HCO3 levels - Also can monitor urine pH to look for success in treating metabolic alkalosis - Look for pH > 7 - In treatment of uric acid stone disease - Want to shift eq: H + urate – uric acid to the left because urate is more soluble - PH goal 6.0-6.5

ReferencesWe considered the complexity of the machinery to excrete ammonium in the context of research on dietary protein and how high protein intake may increase glomerular pressure and contribute to progressive renal disease (many refer to this as the “Brenner hypothesis”). Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal diseaseA trial that studied low protein and progression of CKD The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease(and famously provided data for the MDRD eGFR equation A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study GroupWe wondered about dietary recommendations in CKD. of note, this is best done in the DKD guidelines from KDIGO Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.Joel mentioned this study on red meat and risk of ESKD. Red Meat Intake and Risk of ESRDWe referenced the notion of a plant-based diet. This is an excellent review by Deborah Clegg and Kathleen Hill Gallant. Plant-Based Diets in CKD : Clinical Journal of the American Society of NephrologyHere's the review that Josh mentioned on how the kidney appears to sense pH Molecular mechanisms of acid-base sensing by the kidneyRemarkably, Dr. Dale Dubin put a prize in his ECG book Free Car Prize Hidden in Textbook Read the fine print: Student wins T-birdA review of the role of the kidney in DKA: Diabetic ketoacidosis: Role of the kidney in the acid-base homeostasis re-evaluatedJosh mentioned the effects of infusing large amounts of bicarbonate The effect of prolonged administration of large doses of sodium bicarbonate in man and this study on the respiratory response to a bicarbonate infusion: The Acute Effects In Man Of A Rapid Intravenous Infusion Of Hypertonic Sodium Bicarbonate Solution. Ii. Changes In Respiration And Output Of Carbon DioxideThis is the study of acute respiratory alkalosis in dogs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC293311/?page=1And this is the study of medical students who went to the High Alpine Research Station on the Jungfraujoch in the Swiss Alps https://www.nejm.org/doi/full/10.1056/nejm199105163242003Self explanatory! A group favorite! It Is Chloride Depletion Alkalosis, Not Contraction AlkalosisEffects of chloride and extracellular fluid volume on bicarbonate reabsorption along the nephron in metabolic alkalosis in the rat. Reassessment of the classical hypothesis of the pathogenesis of metabolic alkalosisA review of pendrin's role in volume homeostasis: The role of pendrin in blood pressure regulation | American Journal of Physiology-Renal PhysiologyInfusion of bicarbonate may lead to a decrease in respiratory stimulation but the shift of bicarbonate to the CSF may lag. Check out this review Neural Control of Breathing and CO2 Homeostasis and this classic paper Spinal-Fluid pH and Neurologic Symptoms in Systemic Acidosis.OutlineOutline: Chapter 11- Regulation of Acid-Base Balance- Introduction - Bicarb plus a proton in equilibrium with CO2 and water - Can be rearranged to HH - Importance of regulating pCO2 and HCO3 outside of this equation - Metabolism of carbs and fats results in the production of 15,000 mmol of CO2 per day - Metabolism of protein and other “substances” generates non-carbonic acids and bases - Mostly from sulfur containing methionine and cysteine - And cationic arginine and lysine - Hydrolysis of dietary phosphate that exists and H2PO4– - Source of base/alkali - Metabolism of an ionic amino acids - Glutamate and asparatate - Organic anions going through gluconeogenesis - Glutamate, Citrate and lactate - Net effect on a normal western diet 50-100 mEq of H+ per day - Homeostatic response to these acid-base loads has three stages: - Chemical buffering - Changes in ventilation - Changes in H+ excretion - Example of H2SO4 from oxidation of sulfur containing AA - Drop in bicarb will stimulate renal acid secretion - Nice table of normal cid-base values, arterial and venous- Great 6 bullet points of acid-base on page 328 - Kidneys must excrete 50-100 of non-carbonic acid daily - This occurs by H secretion, but mechanisms change by area of nephron - Not excreted as free H+ due to minimal urine pH being equivalent to 0.05 mmol/L - No H+ can be excreted until virtually all of th filtered bicarb is reabsorbed - Secreted H+ must bind buffers (phosphate, NH3, cr) - PH is main stimulus for H secretion, though K, aldo and volume can affect this.- Renal Hydrogen excretion - Critical to understand that loss of bicarb is like addition of hydrogen to the body - So all bicarb must be reabsorbed before dietary H load can be secreted - GFR of 125 and bicarb of 24 results in 4300 mEq of bicarb to be reabsorbed daily - Reabsorption of bicarb and secretion of H involve H secretion from tubular cells into the lumen. - Thee initial points need to be emphasized - Secreted H+ ion are generated from dissociation of H2O - Also creates OH ion - Which combine with CO2 to form HCO3 with the help of zinc containing intracellular carbonic anhydrase. - This is how the secretion of H+ which creates an OH ultimately produces HCO3 - Different mechanisms for proximal and distal acidification - NET ACID EXCRETION - Free H+ is negligible - So net H+ is TA + NH4 – HCO3 loss - Unusually equal to net H+ load, 50-100 mEq/day - Can bump up to 300 mEq/day if acid production is increased - Net acid excretion can go negative following a bicarb or citrate load - Proximal Acidification - Na-H antiporter (or exchanger) in luminal membrane - Basolateral membrane has a 3 HCO3 Na cotransporter - This is electrogenic with 3 anions going out and only one cation - The Na-H antiporter also works in the thick ascending limb of LOH - How about this, there is also a H-ATPase just like found in the intercalated cells in the proximal tubule and is responsible for about a third of H secretion - And similarly there is also. HCO3 Cl exchanger (pendrin-like) in the proximal tubule - Footnote says the Na- 3HCO3 cotransporter (which moves sodium against chemical gradient NS uses negative charge inside cell to power it) is important for sensing acid-base changes in the cell. - Distal acidification - Occurs in intercalated cells of of cortical and medullary collecting tubule - Three main characteristics - H secretion via active secretory pumps in the luminal membrane - Both H-ATPase and H-K ATPase - H- K ATPase is an exchange pump, k reabsorption - H-K exchange may be more important in hypokalemia rather than in acid-base balance - Whole paragraph on how a Na-H exchanger couldn't work because the gradient that H has to be pumped up is too big. - H-ATPase work like vasopressin with premise H-ATPase sitting on endocarditis vesicles a=which are then inserted into the membrane. Alkalosis causes them to be recycled out of the membrane. - H secretory cells do not transport Na since they have few luminal Na channels, but are assisted by the lumen negative tubule from eNaC. - Minimizes back diffusion of H+ and promotes bicarb resorption - Bicarbonate leaves the cell through HCO3-Cl exchanger which uses the low intracellular Cl concentration to power this process. - Same molecule is found on RBC where it is called band 3 protein - Figure 11-5 is interesting - Bicarbonate resorption - 90% in the first 1-22 mm of the proximal tubule (how long is the proximal tubule?) - Lots of Na-H exchangers and I handed permeability to HCO3 (permeability where?) - Last 10% happens distally mostly TAL LOH via Na-H exchange - And the last little bit int he outer medullary collecting duct. - Carbonic anhydrase and disequilibrium pH - CA plays central role in HCO3 reabsorption - After H is secreted in the proximal tubule it combines with HCO# to form carbonic acid. CA then dehydrates it to CO2 and H2O. (Step 2) - Constantly moving carbonic acid to CO2 and H2O keeps hydrogen combining with HCO3 since the product is rapidly consumed. - This can be demonstrated by the minimal fall in luminal pH - That is important so there is not a luminal gradient for H to overcome in the Na-H exchanger (this is why we need a H-ATPase later) - CA inhibitors that are limited tot he extracellular compartment can impair HCO3 reabsorption by 80%. - CA is found in S1, S2 but not S3 segment. See consequence in figure 11-6. - The disequilibrium comes from areas where there is no CA, the HH formula falls down because one of the assumptions of that formula is that H2CO3 (carbonic acid) is a transient actor, but without CA it is not and can accumulate, so the pKa is not 6.1. - Bicarbonate secretion - Type B intercalated cells - H-ATPase polarity reversed - HCO3 Cl exchanger faces the apical rather than basolateral membrane- Titratable acidity - Weak acids are filtered at the glom and act as buffers in the urine. - HPO4 has PKA of 6.8 making it ideal - Creatinine (pKa 4.97) and uric acid (pKa 5.75) also contribute - Under normal cinditions TA buffers 10-40 mEa of H per day - Does an example of HPO4(2-):H2PO4 (1-) which exists 4:1 at pH of 7.4 (glomerular filtrate) - So for 50 mEq of Phos 40 is HPO4 and 10 is H2PO4 - When pH drops to 6.8 then the ratio is 1:1 so for 50 - So the 50 mEq is 25 and 25, so this buffered an additional 15 mEq of H while the free H+ concentration increased from 40 to 160 nanomol/L so over 99.99% of secreted H was buffered - When pH drops to 4.8 ratio is 1:100 so almost all 50 mEq of phos is H2PO4 and 39.5 mEq of H are buffered. - Acid loading decreases phosphate reabsorption so more is there to act as TA. - Decreases activity of Na-phosphate cotransporter - DKA provides a novel weak acid/buffer beta-hydroxybutyrate (pKa 4.8) which buffers significant amount of acid (50 mEq/d).- Ammonium Excretion - Ability to excrete H+ as ammonium ions adds an important amount of flexibility to renal acid-base regulation - NH3 and NH4 production and excretion can be varied according to physiologic need. - Starts with NH3 production in tubular cells - NH3, since it is neutral then diffuses into the tubule where it is acidified by the low pH to NH4+ - NH4+ is ionized and cannot cross back into the tubule cells(it is trapped in the tubular fluid) - This is important for it acting as an important buffer eve though the pKa is 9.0 - At pH of 6.0 the ratio of NH3 to NH4 is 1:1000 - As the neutral NH3 is converted to NH4 more NH3 from theintracellular compartment flows into the tubular fluid replacing the lost NH3. Rinse wash repeat. - This is an over simplification and that there are threemajor steps - NH4 is produced in early proximal tubular cells - Luminal NH4 is partially reabsorbed in the TAL and theNH3 is then recycled within the renal medulla - The medullary interstitial NH3 reaches highconcentrations that allow NH3 to diffuse into the tubular lumen in the medullary collecting tubule where it is trapped as NH4 by secreted H+ - NH4 production from Glutamine which converts to NH4 and glutamate - Glutamate is converted to alpha-ketoglutarate - Alpha ketoglutarate is converted to 2 HCO3 ions - HCO3 sent to systemic circulation by Na-3 HCO3 transporter - NH4 then secreted via Na-H exchanger into the lumen - NH4 is then reabsorbed by NaK2Cl transporter in TAL - NH4 substitutes for K - Once reabsorbed the higher intracellular pH causes NH4 to convert to NH3 and the H that is removed is secreted through Na-H exchanger to scavenge the last of the filtered bicarb. - NH3 diffuses out of the tubular cells into the interstitium - NH4 reabsorption in the TAL is suppressed by hyperkalemia and stimulated by chronic metabolic acidosis - NH4 recycling promotes acid clearance - The collecting tubule has a very low NH3 concentration - This promotes diffusion of NH3 into the collecting duct - NH3 that goes there is rapidly converted to NH4 allowing more NH3 to diffuse in. - Response to changes in pH - Increased ammonium excretion with two processes - Increased proximal NH4 production - This is delayed 24 hours to 2-3 days depending on which enzyme you look at - Decreased urine pH increases diffusion of ammonia into the MCD - Occurs with in hours of an acid load - Peak ammonium excretion takes 5-6 days! (Fig 11-10) - Glutamine is picked up from tubular fluid but with acidosis get Na dependent peritublar capillary glutamine scavenging too - Glutamine metabolism is pH dependent with increase with academia and decrease with alkalemia - NH4 excretion can go from 30-40 mEq/day to > 300 with severe metabolic acidosis (38 NaBicarb tabs) - Says each NH4 produces equimolar generation of HCO3 but I thought it was two bicarb for every alpha ketoglutarate?- The importance of urine pH - Though the total amount of hydrogren cleared by urine pH is insignificant, an acidic urine pH is essential for driving the reactions of TA and NH4 forward.- Regulation of renal hydrogen excretion - Net acid excretion vary inverse with extracellular pH - Academia triggers proximal and distal acidification - Proximally this: - Increased Na-H exchange - Increased luminal H-ATPase activity - Increased Na:3HCO3 cotransporter on the basolateral membrane - Increased NH4 production from glutamine - In the collecting tubules - Increased H-ATPase - Reduction of tubular pH promotes diffusion of NH3 which gets converted to NH4…ION TRAPPING - Extracellular pH affects net acid excretion through its affect on intracellular pH - This happens directly with respiratory disorders due to movement of CO2 through the lipid bilayer - In metabolic disorders a low extracellular bicarb with cause bicarb to diffuse out of the cell passively, this lowers intracellular pH - If you manipulate both low pCO2 and low Bicarb to keep pH stable there will be no change in the intracellular pH and there is no change in renal handling of acid. It is intracellular pH dependent - Metabolic acidosis - Ramps up net acid secretion - Starts within 24 hours and peaks after 5-6 days - Increase net secretion comes from NH4 - Phosphate is generally limited by diet - in DKA titratable acid can be ramped up - Metabolic alkalosis - Alkaline extracellular pH - Increased bicarb excretion - Decrease reabsorption - HCO3 secretion (pendrin) in cortical collecting tubule - Occurs in cortical intercalated cells able to insert H-ATPase in basolateral cells (rather than luminal membrane) - Normal subjects are able to secrete 1000 mmol/day of bicarb - Maintenance of metabolic alkalosis requires a defect which forces the renal resorption of bicarb - This can be chloride/volume deficiency - Hypokalemia - Hyperaldosteronism - Respiratory acidosis and alkalosis - PCO2 via its effect on intracellular pH is an important determinant of renal acid handling - Ratios he uses: - 3.5 per 10 for respiratory acidosis - 5 per 10 for respiratory alkalosis - Interesting paragraph contrasting the response to chronic metabolic acidosis vs chronic respiratory acidosis - Less urinary ammonium in respiratory acidosis - Major differences in proximal tubule cell pH - In metabolic acidosis there is decreased bicarb load so less to be reabsorbed proximally - In respiratory acidosis the increased serum bicarb increases the amount of bicarb that must be reabsorbed proximally - The increased activity of Na-H antiporter returns tubular cell pH to normal and prevents it from creating increased urinary ammonium - Mentions that weirdly more mRNA for H-Na antiporter in metabolic acidosis than in respiratory acidosis - Net hydrogen excretion varies with effective circulating volume - Starts with bicarb infusions - Normally Tm at 26 - But if you volume deplete the patient with diuretics first this increases to 35+ - Four factors explain this increased Tm for bicarb with volume deficiency - Reduced GFR - Activation of RAAS - Ang2 stim H-Na antiporter proximally - Ang2 also stimulates Na-3HCO3 cotransporter on basolateral membrane - Aldosterone stimulates H-ATPase in distal nephron - ALdo stimulates Cl HCO3 exchanger on basolateral membrane - Aldo stimulates eNaC producing tubular lumen negative charge to allow H secretion to occur and prevents back diffusion - Hypochloremia - Increases H secretion by both Na-dependent and Na-independent methods - If Na is 140 and Cl is 115, only 115 of Na can be reabsorbed as NaCl, the remainder must be reabsorbed with HCO3 or associated with secretion of K or H to maintained electro neutrality - This is enhanced with hypochloridemia - Concurrent hypokalemia - Changes in K lead to trans cellular shifts that affect inctracellular pH - Hypokalemia causes K out, H in and in the tubular cell the cell acts if there is systemic acidosis and increases H secretion (and bicarbonate resorption) - PTH - Decreases proximal HCO3 resorption - Primary HyperCard as cause of type 2 RTA - Does acidosis stim PTH or does PTH stim net acid excretion

The Channelers went where no nephrology podcasters have gone before, recording in front of a live audience at the National Kidney Foundation Clinical Meeting in Austin. We had all eight Channelers doing a live podcast.We did a Freely Filtered-inspired draft of the best diuretics.The draft order:Leticia Rolon Anna Gaddy Joel TopfRoger Rodby Josh Waitzman Amy Yau JC Velez And Melanie HoenigReferencesJC Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney DiseaseIntravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experienceRapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following TolvaptanTolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for HyponatremiaJosh Review on amiloride development https://pubmed.ncbi.nlm.nih.gov/7039345/Toad bladder: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1351665/Amiloride derivatives that inhibit flagella: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544414/Amiloride as taste sensor: https://www.science.org/doi/10.1126/science.6691151Batlle on diabetes Insipidus: https://www.nejm.org/doi/full/10.1056/NEJM198502143120705?query=recirc_curatedRelated_articleAmiloride + ddavp for DI https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518801/Amy Treatment of refractory congestive heart failure and normokalemic hypochloremic alkalosis with acetazolamide and spironolactone.Acetazolamide reversibly inhibits water conduction by aquaporin-4Inhibition of Human Aquaporin-1 Water Channel Activity by Carbonic Anhydrase InhibitorsAcetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes InsipidusAcetazolamide in Lithium-Induced Nephrogenic Diabetes InsipidusIn Vivo Antibacterial Activity of AcetazolamideRoger50th anniversary of aldosteroneJoelSotagliflozin in Patients with Diabetes and Recent Worsening Heart FailureThe SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trialEffects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF)Empagliflozin and Heart failure: Diuretic and Cardiorenal EffectsAnnaClinical Results of Treatment of Diabetes Insipidus with Drugs of the Chlorothiazide SeriesTreatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amilorideInfluence of renal nerves and sodium balance on the acute antidiuretic effect of bendroflumethiazide in rats with diabetes insipidusAntidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channelMajor Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs DiureticWalsh AC, Moyes A. Intractable Congestive Heart Failure Successfully Treated With Southey Tubes. Can Med Assoc J. 1964 Jun 13;90(24):1375-6.Godwin TF, Gunton RW. Clinical trial of a new diuretic, furosemide: comparison with hydrochlorothiazide and mercaptomerin. Can Med Assoc J. 1965 Dec 18;93(25):1296-300.Gerber JG. Role of prostaglandins in the hemodynamic and tubular effects of furosemide. Fed Proc. 1983 Apr;42(6):1707-10.Schlatter E, Salomonsson M, Persson AE, Greger R. Macula densa cells sense luminal NaCl concentration via furosemide sensitive Na+2Cl-K+ cotransport. Pflugers Arch. 1989 Jul;414(3):286-90. doi: 10.1007/BF00584628.

ReferencesWe considered the effect of a high protein diet and potential metabolic acidosis on kidney function. This review is of interest by Donald Wesson, a champion for addressing this issue and limiting animal protein: Mechanisms of Metabolic Acidosis-Induced Kidney Injury in Chronic Kidney DiseaseHostetter explored the effect of a high protein diet in the remnant kidney model with 1 ¾ nephrectomy. Rats with reduced dietary acid load (by bicarbonate supplementation) had less tubular damage. Chronic effects of dietary protein in the rat with intact and reduced renal massWesson explored treatment of metabolic acidosis in humans with stage 3 CKD in this study. Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rateIn addition to the effect of metabolic acidosis from a diet high in animal protein, this diet also leads to hyperfiltration. This was demonstrated in normal subjects; ingesting a protein diet had a significantly higher creatinine clearance than a comparable group of normal subjects ingesting a vegetarian diet. Renal functional reserve in humans: Effect of protein intake on glomerular filtration rate.This finding has been implicated in Brenner's theory regarding hyperfiltration: The hyperfiltration theory: a paradigm shift in nephrologyOne of multiple publications from Dr. Nimrat Goraya whom Joel mentioned in the voice over: Dietary Protein as Kidney Protection: Quality or Quantity?We wondered about the time course in buffering a high protein meal (and its subsequent acid load on ventilation) and Amy found this report:Effect of Protein Intake on Ventilatory Drive | Anesthesiology | American Society of Anesthesiologists Roger mentioned that the need for acetate to balance the acid from amino acids in parenteral nutrition was identified in pediatrics perhaps because infants may have reduced ability to generate acid. Randomised controlled trial of acetate in preterm neonates receiving parenteral nutrition - PMCHe also recommended an excellent review on the complications of parenteral nutrition by Knochel https://www.kidney-international.org/action/showPdf?pii=S0085-2538%2815%2933384-6 which explained that when the infused amino acids disproportionately include cationic amino acids, metabolism led to H+ production. This is typically mitigated by preparing a solution that is balanced by acetate. Amy mentioned this study that explored the effect of protein intake on ventilation: Effect of Protein Intake on Ventilatory Drive | Anesthesiology | American Society of AnesthesiologistsAnna and Amy reminisced about a Skeleton Key Group Case from the renal fellow network Skeleton Key Group: Electrolyte Case #7JC wondered about isolated defects in the proximal tubule and an example is found here: Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalitiesAnna's Voiceover re: Gastric neobladder → metabolic alkalosis and yes, dysuria. The physiology of gastrocystoplasty: once a stomach, always a stomach but not as common as you might think Gastrocystoplasty: long-term complications in 22 patientsSjögren's syndrome has been associated with acquired distal RTA and in some cases, an absence of the H+ ATPase, presumably from autoantibodies to this transporter. Here's a case report: Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosisCan't get enough disequilibrium pH? Check this out- Spontaneous luminal disequilibrium pH in S3 proximal tubules. Role in ammonia and bicarbonate transport.Acetazolamide secretion was studied in this report Concentration-dependent tubular secretion of acetazolamide and its inhibition by salicylic acid in the isolated perfused rat kidney. | Drug Metabolism & DispositionIn this excellent review, David Goldfarb tackles the challenging case of a A Woman with Recurrent Calcium Phosphate Kidney Stones (spoiler alert, many of these patients have incomplete distal RTA and this problem is hard to treat). Molecular mechanisms of renal ammonia transport excellent review from David Winer and Lee Hamm. OutlineOutline: Chapter 11- Regulation of Acid-Base Balance- Introduction - Bicarb plus a proton in equilibrium with CO2 and water - Can be rearranged to HH - Importance of regulating pCO2 and HCO3 outside of this equation - Metabolism of carbs and fats results in the production of 15,000 mmol of CO2 per day - Metabolism of protein and other “substances” generates non-carbonic acids and bases - Mostly from sulfur containing methionine and cysteine - And cationic arginine and lysine - Hydrolysis of dietary phosphate that exists and H2PO4– - Source of base/alkali - Metabolism of an ionic amino acids - Glutamate and asparatate - Organic anions going through gluconeogenesis - Glutamate, Citrate and lactate - Net effect on a normal western diet 50-100 mEq of H+ per day - Homeostatic response to these acid-base loads has three stages: - Chemical buffering - Changes in ventilation - Changes in H+ excretion - Example of H2SO4 from oxidation of sulfur containing AA - Drop in bicarb will stimulate renal acid secretion - Nice table of normal cid-base values, arterial and venous- Great 6 bullet points of acid-base on page 328 - Kidneys must excrete 50-100 of non-carbonic acid daily - This occurs by H secretion, but mechanisms change by area of nephron - Not excreted as free H+ due to minimal urine pH being equivalent to 0.05 mmol/L - No H+ can be excreted until virtually all of th filtered bicarb is reabsorbed - Secreted H+ must bind buffers (phosphate, NH3, cr) - PH is main stimulus for H secretion, though K, aldo and volume can affect this.- Renal Hydrogen excretion - Critical to understand that loss of bicarb is like addition of hydrogen to the body - So all bicarb must be reabsorbed before dietary H load can be secreted - GFR of 125 and bicarb of 24 results in 4300 mEq of bicarb to be reabsorbed daily - Reabsorption of bicarb and secretion of H involve H secretion from tubular cells into the lumen. - Thee initial points need to be emphasized - Secreted H+ ion are generated from dissociation of H2O - Also creates OH ion - Which combine with CO2 to form HCO3 with the help of zinc containing intracellular carbonic anhydrase. - This is how the secretion of H+ which creates an OH ultimately produces HCO3 - Different mechanisms for proximal and distal acidification - NET ACID EXCRETION - Free H+ is negligible - So net H+ is TA + NH4 – HCO3 loss - Unusually equal to net H+ load, 50-100 mEq/day - Can bump up to 300 mEq/day if acid production is increased - Net acid excretion can go negative following a bicarb or citrate load - Proximal Acidification - Na-H antiporter (or exchanger) in luminal membrane - Basolateral membrane has a 3 HCO3 Na cotransporter - This is electrogenic with 3 anions going out and only one cation - The Na-H antiporter also works in the thick ascending limb of LOH - How about this, there is also a H-ATPase just like found in the intercalated cells in the proximal tubule and is responsible for about a third of H secretion - And similarly there is also. HCO3 Cl exchanger (pendrin-like) in the proximal tubule - Footnote says the Na- 3HCO3 cotransporter (which moves sodium against chemical gradient NS uses negative charge inside cell to power it) is important for sensing acid-base changes in the cell. - Distal acidification - Occurs in intercalated cells of of cortical and medullary collecting tubule - Three main characteristics - H secretion via active secretory pumps in the luminal membrane - Both H-ATPase and H-K ATPase - H- K ATPase is an exchange pump, k reabsorption - H-K exchange may be more important in hypokalemia rather than in acid-base balance - Whole paragraph on how a Na-H exchanger couldn't work because the gradient that H has to be pumped up is too big. - H-ATPase work like vasopressin with premise H-ATPase sitting on endocarditis vesicles a=which are then inserted into the membrane. Alkalosis causes them to be recycled out of the membrane. - H secretory cells do not transport Na since they have few luminal Na channels, but are assisted by the lumen negative tubule from eNaC. - Minimizes back diffusion of H+ and promotes bicarb resorption - Bicarbonate leaves the cell through HCO3-Cl exchanger which uses the low intracellular Cl concentration to power this process. - Same molecule is found on RBC where it is called band 3 protein - Figure 11-5 is interesting - Bicarbonate resorption - 90% in the first 1-22 mm of the proximal tubule (how long is the proximal tubule?) - Lots of Na-H exchangers and I handed permeability to HCO3 (permeability where?) - Last 10% happens distally mostly TAL LOH via Na-H exchange - And the last little bit int he outer medullary collecting duct. - Carbonic anhydrase and disequilibrium pH - CA plays central role in HCO3 reabsorption - After H is secreted in the proximal tubule it combines with HCO# to form carbonic acid. CA then dehydrates it to CO2 and H2O. (Step 2) - Constantly moving carbonic acid to CO2 and H2O keeps hydrogen combining with HCO3 since the product is rapidly consumed. - This can be demonstrated by the minimal fall in luminal pH - That is important so there is not a luminal gradient for H to overcome in the Na-H exchanger (this is why we need a H-ATPase later) - CA inhibitors that are limited tot he extracellular compartment can impair HCO3 reabsorption by 80%. - CA is found in S1, S2 but not S3 segment. See consequence in figure 11-6. - The disequilibrium comes from areas where there is no CA, the HH formula falls down because one of the assumptions of that formula is that H2CO3 (carbonic acid) is a transient actor, but without CA it is not and can accumulate, so the pKa is not 6.1. - Bicarbonate secretion - Type B intercalated cells - H-ATPase polarity reversed - HCO3 Cl exchanger faces the apical rather than basolateral membrane- Titratable acidity - Weak acids are filtered at the glom and act as buffers in the urine. - HPO4 has PKA of 6.8 making it ideal - Creatinine (pKa 4.97) and uric acid (pKa 5.75) also contribute - Under normal cinditions TA buffers 10-40 mEa of H per day - Does an example of HPO4(2-):H2PO4 (1-) which exists 4:1 at pH of 7.4 (glomerular filtrate) - So for 50 mEq of Phos 40 is HPO4 and 10 is H2PO4 - When pH drops to 6.8 then the ratio is 1:1 so for 50 - So the 50 mEq is 25 and 25, so this buffered an additional 15 mEq of H while the free H+ concentration increased from 40 to 160 nanomol/L so over 99.99% of secreted H was buffered - When pH drops to 4.8 ratio is 1:100 so almost all 50 mEq of phos is H2PO4 and 39.5 mEq of H are buffered. - Acid loading decreases phosphate reabsorption so more is there to act as TA. - Decreases activity of Na-phosphate cotransporter - DKA provides a novel weak acid/buffer beta-hydroxybutyrate (pKa 4.8) which buffers significant amount of acid (50 mEq/d).- Ammonium Excretion - Ability to excrete H+ as ammonium ions adds an important amount of flexibility to renal acid-base regulation - NH3 and NH4 production and excretion can be varied according to physiologic need. - Starts with NH3 production in tubular cells - NH3, since it is neutral then diffuses into the tubule where it is acidified by the low pH to NH4+ - NH4+ is ionized and cannot cross back into the tubule cells(it is trapped in the tubular fluid) - This is important for it acting as an important buffer eve though the pKa is 9.0 - At pH of 6.0 the ratio of NH3 to NH4 is 1:1000 - As the neutral NH3 is converted to NH4 more NH3 from theintracellular compartment flows into the tubular fluid replacing the lost NH3. Rinse wash repeat. - This is an over simplification and that there are threemajor steps - NH4 is produced in early proximal tubular cells - Luminal NH4 is partially reabsorbed in the TAL and theNH3 is then recycled within the renal medulla - The medullary interstitial NH3 reaches highconcentrations that allow NH3 to diffuse into the tubular lumen in the medullary collecting tubule where it is trapped as NH4 by secreted H+ - NH4 production from Glutamine which converts to NH4 and glutamate - Glutamate is converted to alpha-ketoglutarate - Alpha ketoglutarate is converted to 2 HCO3 ions - HCO3 sent to systemic circulation by Na-3 HCO3 transporter - NH4 then secreted via Na-H exchanger into the lumen - NH4 is then reabsorbed by NaK2Cl transporter in TAL - NH4 substitutes for K - Once reabsorbed the higher intracellular pH causes NH4 to convert to NH3 and the H that is removed is secreted through Na-H exchanger to scavenge the last of the filtered bicarb. - NH3 diffuses out of the tubular cells into the interstitium - NH4 reabsorption in the TAL is suppressed by hyperkalemia and stimulated by chronic metabolic acidosis - NH4 recycling promotes acid clearance - The collecting tubule has a very low NH3 concentration - This promotes diffusion of NH3 into the collecting duct - NH3 that goes there is rapidly converted to NH4 allowing more NH3 to diffuse in. - Response to changes in pH - Increased ammonium excretion with two processes - Increased proximal NH4 production - This is delayed 24 hours to 2-3 days depending on which enzyme you look at - Decreased urine pH increases diffusion of ammonia into the MCD - Occurs with in hours of an acid load - Peak ammonium excretion takes 5-6 days! (Fig 11-10) - Glutamine is picked up from tubular fluid but with acidosis get Na dependent peritublar capillary glutamine scavenging too - Glutamine metabolism is pH dependent with increase with academia and decrease with alkalemia - NH4 excretion can go from 30-40 mEq/day to > 300 with severe metabolic acidosis (38 NaBicarb tabs) - Says each NH4 produces equimolar generation of HCO3 but I thought it was two bicarb for every alpha ketoglutarate?- The importance of urine pH - Though the total amount of hydrogren cleared by urine pH is insignificant, an acidic urine pH is essential for driving the reactions of TA and NH4 forward.- Regulation of renal hydrogen excretion - Net acid excretion vary inverse with extracellular pH - Academia triggers proximal and distal acidification - Proximally this: - Increased Na-H exchange - Increased luminal H-ATPase activity - Increased Na:3HCO3 cotransporter on the basolateral membrane - Increased NH4 production from glutamine - In the collecting tubules - Increased H-ATPase - Reduction of tubular pH promotes diffusion of NH3 which gets converted to NH4…ION TRAPPING - Extracellular pH affects net acid excretion through its affect on intracellular pH - This happens directly with respiratory disorders due to movement of CO2 through the lipid bilayer - In metabolic disorders a low extracellular bicarb with cause bicarb to diffuse out of the cell passively, this lowers intracellular pH - If you manipulate both low pCO2 and low Bicarb to keep pH stable there will be no change in the intracellular pH and there is no change in renal handling of acid. It is intracellular pH dependent - Metabolic acidosis - Ramps up net acid secretion - Starts within 24 hours and peaks after 5-6 days - Increase net secretion comes from NH4 - Phosphate is generally limited by diet - in DKA titratable acid can be ramped up - Metabolic alkalosis - Alkaline extracellular pH - Increased bicarb excretion - Decrease reabsorption - HCO3 secretion (pendrin) in cortical collecting tubule - Occurs in cortical intercalated cells able to insert H-ATPase in basolateral cells (rather than luminal membrane) - Normal subjects are able to secrete 1000 mmol/day of bicarb - Maintenance of metabolic alkalosis requires a defect which forces the renal resorption of bicarb - This can be chloride/volume deficiency - Hypokalemia - Hyperaldosteronism - Respiratory acidosis and alkalosis - PCO2 via its effect on intracellular pH is an important determinant of renal acid handling - Ratios he uses: - 3.5 per 10 for respiratory acidosis - 5 per 10 for respiratory alkalosis - Interesting paragraph contrasting the response to chronic metabolic acidosis vs chronic respiratory acidosis - Less urinary ammonium in respiratory acidosis - Major differences in proximal tubule cell pH - In metabolic acidosis there is decreased bicarb load so less to be reabsorbed proximally - In respiratory acidosis the increased serum bicarb increases the amount of bicarb that must be reabsorbed proximally - The increased activity of Na-H antiporter returns tubular cell pH to normal and prevents it from creating increased urinary ammonium - Mentions that weirdly more mRNA for H-Na antiporter in metabolic acidosis than in respiratory acidosis - Net hydrogen excretion varies with effective circulating volume - Starts with bicarb infusions - Normally Tm at 26 - But if you volume deplete the patient with diuretics first this increases to 35+ - Four factors explain this increased Tm for bicarb with volume deficiency - Reduced GFR - Activation of RAAS - Ang2 stim H-Na antiporter proximally - Ang2 also stimulates Na-3HCO3 cotransporter on basolateral membrane - Aldosterone stimulates H-ATPase in distal nephron - ALdo stimulates Cl HCO3 exchanger on basolateral membrane - Aldo stimulates eNaC producing tubular lumen negative charge to allow H secretion to occur and prevents back diffusion - Hypochloremia - Increases H secretion by both Na-dependent and Na-independent methods - If Na is 140 and Cl is 115, only 115 of Na can be reabsorbed as NaCl, the remainder must be reabsorbed with HCO3 or associated with secretion of K or H to maintained electro neutrality - This is enhanced with hypochloridemia - Concurrent hypokalemia - Changes in K lead to trans cellular shifts that affect inctracellular pH - Hypokalemia causes K out, H in and in the tubular cell the cell acts if there is systemic acidosis and increases H secretion (and bicarbonate resorption) - PTH - Decreases proximal HCO3 resorption - Primary HyperCard as cause of type 2 RTA - Does acidosis stim PTH or does PTH stim net acid excretion

References for Chapter 10We did not mention many references in our discussion today but our listeners may enjoy some of the references below. Effects of pH on Potassium: New Explanations for Old Observations - PMC although the focus of this article is on potassium, this elegant review by Aronson and Giebisch reviews intracellular shifts as it relates to pH and K+.Josh swooned for Figure 10-1 is this right? Which figure was it? which shows the relationship between [H+] and pH. You can find this figure in the original reference from Halperin ML and others, Figure 1 here. Factors That Control the Effect of pH on Glycolysis in Leukocytes Here's Leticia Rolon's favorite Henderson-Hasselbalch calculator website: ​​Henderson-Hasselbalch Calculator | Buffer Solutions [hint! for this site, use the bicarbonate (or “total CO2”) for A- and PCO2 for the HA] There's also a cooking tab for converting units! Fundamentals of Arterial Blood Gas Interpretation - PMC this review published posthumously from the late but beloved Jerry Yee and his group at Henry Ford Hospital, explores the details and underpinnings of our understandings of arterial blood gas interpretation (and this also addresses how our colleagues in clinical chemistry measure total CO2 - which JC referenced- but JC said “machine” and our colleagues prefer the word “instrument.”)Amy went deep on bicarbonate in respiratory acidosis. Here are her refs:Sodium bicarbonate therapy for acute respiratory acidosisSodium Bicarbonate in Respiratory AcidosisBicarbonate therapy in severe metabolic acidosisEffect of Intravenous Sodium Bicarbonate on Ventilation, Gas Exchange, and Acid-Base Balance in Patients with Chronic Pulmonary InsufficiencyBicarbonate Therapy in Severe Metabolic Acidosis | American Society of Nephrology this review article from Sabatini and Kurtzman addresses the issues regarding bicarbonate therapy including theoretical intracellular acidosis. Bicarbonate in DKA? Don't do it: Bicarbonate in diabetic ketoacidosis - a systematic review Here's a review from Bushinsky and Krieger on the effect acidosis on bone https://www.sciencedirect.com/science/article/abs/pii/S0085253822002174Here is the primary resource that Anna used in here investigation of meat replacements Nutritional Composition of Novel Plant-Based Meat Alternatives and Traditional Animal-Based MeatsWe enjoyed this paper that Dr. Rose references from the Journal of Clinical Investigation 1955 in which investigators infused HCl into nephrectomized dogs and observed changes in extracellular ions. https://www.jci.org/articles/view/103073/pdWe wondered about the amino acids/protein in some available meat alternatives they are explored in this article in the journal Amino Acids: Protein content and amino acid composition of commercially available plant-based protein isolates - PMC and you may enjoy this exploration of the nutritional value of these foods: Full article: Examination of the nutritional composition of alternative beef burgers available in the United StatesOutlineChapter 10: Acid-Base Physiology - H concentration regulated tightly - Normal H+ is 40 nm/L - This one millionth the concentration of Na and K - It needs to be this dilute because H+ fucks shit up - Especially proteins - Cool foot note H+ actually exists as H3O+ - Under normal conditions the H+ concentration varies little from normal due to three steps - Chemical buffering by extracellular and intracellular bufffers - Control of partial pressure of CO2 by alterations of alveolar ventilation - Control of plasma bicarbonate by changes in renal H+ excretion - Acid and bases - Use definition by Bronsted - Acid can donate protons - Base can accept protons - There are two classes of acids** - Carbonic acid H2CO3 - Each day 15000 mmol of CO2 are generated - CO2 not acid but combines with water to form carbonic acid H2CO3 - CO2 cleared by the lungs - Noncarbonic acid - Formed from metabolism of protein. Sulfur containing AA generate H2SO4. Only 50-100 mEq of acid produced from these sources. - Cleared by the kidneys - Law of Mass Action - Velocity of reaction proportional to the product of the concentrations of the reactants - Goes through mass action formula for water - Concludes that water has H of 155 nanoM/L, more than the 40 in plasma - Says you can do the same mass experiment for every acid in the body - Can do it also for bases but he is not going to. - Acids and Bases can be strong or weak - Strong acids completely dissociate - Weak acids not so much - H2PO4 is only 80% dissociated - Weak acids are the principle buffers in the body - Then he goes through how H is measured in the blood and it becomes clear why pH is a logical way to measure. - Then there is a lot of math - HH equation - Derives it - Then uses it to look at phos. Very interesting application - Buffers - Goes tot he phosphate well again. Amazing math describing how powerful buffers can be - Big picture the closer the pKa is to the starting pH the better buffer, i.e. it can absorb lots of OH or H without appreciably changing pH - HCO3 CO2 system - H2CO3 to H + HCO3 has a PKA of 2.72 but then lots of Math and the bicarb buffer system has a pKa of 6.1 - But the real power of the bicarb buffer is that it is not a sealed system. The ability to ventilate and keep CO2 constant increases the buffering efficiency by 11 fold and the ability to lower the CO2 below normal increases 18 fold. - Isohydric principle - There is only one hydrogen ion concentration and since that is a critical part of the buffer equation, all buffer eq are linked and you can understand all of them by understanding one of them. So we just can look at bicarb and understand the totality of acid base. - Bicarb is the most important buffer because - High concentration in plasma - Ability for CO2 to ventilate - Other buffers include - Bone - Bone is more than just inorganic reaction - Live bone releases more calcium in response to an acid load than dead bone - More effect with metabolic acidosis than respiratory acidosis - Hgb - Phosphate - Protein

References for Chapter 9One of the few papers that Rose wrote as a single author explores electrolyte free water clearance. This seminal paper explores the issue in greater detail than the book. A New approach to disturbances in the plasma sodium concentrationWondering about the volume of sweat? Josh taught us that the volume of “transepidermal volume loss” is not affected by humidity https://www.jidonline.org/article/S0022-202X(15)48145-X/pdf but is greatly affected by temperature: Skin temperature and transepidermal water lossRegarding normal sweat physiology, there is a nice review (with figures!) titled Physiological mechanisms determining sweat composition which describes all the important cells and channels which make up sweat glands. And an important follow on paper titled Higher Bioelectric Potentials due to Decreased Chloride Absorption in the Sweat Glands of Patients with Cystic Fibrosis describing specifically the sweat characteristics of patients with cystic fibrosis.Melanie was enchanted by work from RA McCance who did early experiments to induce sodium deficiency using very low sodium diets and a homemade sauna-like tent. His musings are fascinating. Lancet 1936 Experimental human salt deficiency MEDICAL PROBLEMS IN MINERAL METABOLISMAge-related decline in urine concentration may not be universal: Comparative study from the US and two small-scale societies from Jeff Sands (of urea transport fame!)In this initial report, after continually water loading 21 volunteers, the younger group (mean age 31) had a urine osmolality of 52 mOsm/kg compared to in the older group (mean age 84). Influence of age, renal disease, hypertension, diuretics, and calcium on the antidiuretic responses to suboptimal infusions of vasopressin. In a later report older subjects (mean age 72) vs younger controls (mean age 26) drank 20 ml/kg over 40 minutes. The younger group excreted more of the water in the first 2 hours and had a lower mean urine osmolality 86 vs 112 mOsm/kg compared to the older participants. Age-associated Alterations in Thirst and Arginine Vasopressin in Response to a Water or Sodium Load Howard Furst suggests the urine to plasma electrolyte ratio as a simpler strategy to consider the free water clearance: https://nephrology.edublogs.org/files/2014/03/Water-Restriction-in-Hyponatremia1-1eb8n40.pdf or via pubmed: The urine/plasma electrolyte ratio: a predictive guide to water restrictionRapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following TolvaptanInfoSnack picture of pre and post tolvaptan

References for chapter 8Robert Schrier proposed a unifying hypothesis to explain the sodium retention seen in edematous states like cirrhosis and heart failure, coining the term effective arterial blood volume (EABV). An open access review in JASN 2007 can be found here: https://jasn.asnjournals.org/content/18/7/2028#ref-3 John P PetersASN Annual Award: https://www.asn-online.org/about/awards/award.aspx?awh_key=0ea83199-f86d-4506-9507-d7e4ce688cb4Short article discussing contributions of Dr. Peters by mentees Dr. Franklin Epstein and Dr. Donald Seldin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588700/ and https://pubmed.ncbi.nlm.nih.gov/12097739/Epstein FH et al. Studies of the antidiuresis of quiet standing: the importance of changes in plasma volume and glomerular filtration. JCI 1950. In this classic report, investigators studied their own sodium excretion supine, standing and with a variety of maneuvers (saline or albumin infusion) and showed that urinary sodium excretion is limited in the upright position compared to supine position. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC436228/pdf/jcinvest00414-0077.pdfAn interesting review of early concepts on hypertension feature notes on John J Hay and Paul Dudley White. The former was known to say, “The greatest danger to a man with high blood pressure lies in its discovery because then some fool is certain to try and reduce it!” and the latter has been quoted as saying that hypertension might be compensatory but apparently, these quotes are out of context. To find out what they really said, check out: Elias MF and Goodell AL. Setting the record straight for two heroes in hypertension John J Hay and Paul Dudley White. J Clin Hypertens 2019 https://onlinelibrary.wiley.com/doi/epdf/10.1111/jch.13650 VA Cooperative Trial was an important study to establish the hypertension should, in fact, be treated The VA Cooperative Study and the Beginning of Routine Hypertension Screening, 1964-1980 This study was stopped after only 18 months because of an excess of deaths in the untreated group who had a mean diastolic BP of 115 mmHg. For a long time, only the diastolic BP was felt to be important until the Systolic Hypertension in Elderly Patients (“SHEP study”) clarified that treatment of isolated systolic hypertension is also importantPrevention of Stroke by Antihypertensive Drug Treatment in Older Persons With Isolated Systolic HypertensionWe continued to try to grapple with the work of Jens Titze on sodium which turns many of our assumptions about sodium upside down. His team studied astronauts on a long term high sodium diet and found an unexpected weekly (circaseptan) rhythm seemingly related inversely to aldosterone and directly with cortisol. His work also probes our notion of body sodium content. For a great first hand read, check out Dr TItze's review in Kidney International 2014 which he aptly dubs, “Spooky Sodium Balence.” https://www.sciencedirect.com/science/article/pii/S0085253815562807Epstein M. The cardiovascular and renal effects of head-out of water Immersion in Man. Circulation Research 1976 Cardiovascular and renal effects of head-out water immersion in man: application of the model in the assessment of volume homeosSpace flight is an exaggeration of the water immersion experiments. Astronauts on either a low or normal sodium diet had a reset of natriuetic peptides. A Salty Tale: Study Examines Sodium Regulation in Space and Natriuretic Peptide Resetting in Astronauts | CirculationBaroreceptors feature mechanically activated ion channels called PIEZO1 and PIEZO2. Zeng W, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM. PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102061/We also relearned an unfortunate truth: lots of folks pee in pools. De Laat et al. Water Res. 2011. Concentration levels of urea in swimming pool water and reactivity of chlorine with urea At the American College of Cardiology meeting in April, investigators shared the news that the combination of an ARB with new class of drugs called angiotensin receptor neprilysin inhibitor (ARNI) was not superior to ACE inhibitors at reduction of heart failure following acute MI. Here's the press release for the PARADISE-MI trial. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial InfarctionA series of elegant experiments by Alicia McDonald's team to characterize pressure natriuresis. In these studies, they induce hypertension by constriction of the superior mesenteric artery, the celiac artery and the infrarenal aorta (essentially increasing afterload without directly altering the blood flow to the kidney). With this maneuver, the blood pressure of the experimental animal rises, urinary sodium excretion increases and then they demonstrate a shift in the Na-H ATPase from the apical membrane to intracellular vesicles in the proximal tubule and a shift in NCC from the luminal membrane to the intracellular vesicles in the distal tubules. Yang L et. al Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity. Am J Physiol Renal 2002 https://journals.physiology.org/doi/full/10.1152/ajprenal.00298.2001?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.orgLee DH Riquier ADM, Yang LE, Leong PK, Maunsbach and McDonough AA. Acute hypertension provokes acute trafficking of distal tubule NaCl (NCC) to subapical cytoplasmic vesicles. Am J Physiol Renal Physiol. 2009 Acute hypertension provokes acute trafficking of distal tubule Na-Cl cotransporter (NCC) to subapical cytoplasmic vesicles This review in KI reports is also worth a read McDonough AA. Maintaining Balance under pressure-hypertension and the proximal tubule. 2015 ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

Chapter 7ReferencesSands JM, Blount MA and Klein JD. Regulation of Renal Urea Transport by Vasopressin. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116377/In this invited piece, Sands and colleagues explain that although urea is permeable across membranes, this is slow, thus urea transporters in the kidney, under control of vasopressin, are needed to facilitate transport and create the medullary gradient. Text book using 20% of extracellular compartment being in the intravascular compartment. https://courses.lumenlearning.com/ap2/chapter/body-fluids-and-fluid-compartments-no-content/ another one: https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Anatomy_and_Physiology_(Boundless)/25%3A_Body_Fluids_and_Acid-Base_Balance/25.2%3A_Body_Fluids/25.2B%3A_Fluid_Compartments The chapter I wrote where I went through the math in figure 7-3. It was a major revelation to me: https://docs.google.com/document/d/17BM1xihvlztuQlU8GVNhEDoPLzr6GounHYZAtVUkLvw/edit?usp=sharing Association Between ICU-Acquired Hypernatremia and In-Hospital Mortality https://journals.lww.com/ccejournal/fulltext/2020/12000/association_between_icu_acquired_hypernatremia_and.26.aspx Rate of Correction of Hypernatremia and Health Outcomes in Critically Ill Patients https://pubmed.ncbi.nlm.nih.gov/30948456/ Edelman IS, Leibman J, O'Meara MP and Birkenfeld LW. Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. JCI 1958. This classic paper calculates the total body exchangeable sodium and potassium and establishes the relationship between these. Understanding this painstacking work helps understand the effect of supplementing potassium in the setting of hyponatremia. https://dm5migu4zj3pb.cloudfront.net/manuscripts/103000/103712/cache/103712.1-20201218131357-covered-e0fd13ba177f913fd3156f593ead4cfd.pdfEdelman is the Root of Almost All Good in Nephrology https://www.renalfellow.org/2014/11/20/edelman-is-root-of-almost-all-good-in/ Jens Titze and his team published a pair of articles that shocked those interested in salt and water in JCI in 2017. High Salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation https://www.jci.org/articles/view/88532Increased salt consumption induces body water conservation and decreases fluid intake https://www.jci.org/articles/view/88530in this exciting exploration of the basic assumptions that we hold true regarding salt and water (and staring Russian cosmonauts and an incredible controlled simulation of salt and water intake), Titze shows that high sodium intake does not simply drive water consumption (as we usually teach) but instead leads to a complex hormonal and metabolic response (even with diurnal variation!) and results in body water conservation and decreased water consumption. And accompanying editorial from Mark Zeidel: salt and water, not so simple. https://www.jci.org/articles/view/94004In addition, Titze and others have done interesting work on sodium deposition in tissues where it may also be a source for systemic inflammation.https://pubmed.ncbi.nlm.nih.gov/28154199/Jens Titze talking about salt, water, thirsting a TEDx talk. https://www.youtube.com/watch?v=jQQPBmnIuCY A discussion/debate of the overfill vs. underfill theory of edema in the nephrotic syndrome (hint- overfill theory triumphs) would be incomplete without a reference to congenital analbuminemia. This reference from Frontiers in Genetics explores the diagnosis, phenotype and molecular genetics and reveal that patients tend to have only mild edema but severe hyperlipidemia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478806/The finding that proteinuria can directly lead to sodium retention based on a study when puromycin aminoglycoside induced proteinuria of one kidney lead to sodium retention by that kidney which was localized to the distal nephron. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC436841/?page=9Plasmin may be the culprit at the level of the epithelial sodium channel based on Tom Kleyman's work: https://jasn.asnjournals.org/content/20/2/233Amiloride may help! (stay tuned for amiloride in a future episode) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016639/An old favorite of JC's from the Kidney International feature which debates the cause of edema in the nephrotic syndrome.https://www.sciencedirect.com/science/article/pii/S0085253815583075Under protest, we hobbled through a discussion of the Gibbs Donnan affect even encouraged by one of Amy's fellows based on this article from QJM: https://academic.oup.com/qjmed/article/101/10/827/1520972 suggesting that our understanding of the role of hyponatremia in fractures might be all wrong- it could be related to hypoalbuminemia.

Chapter 6 part 2. ReferencesJosh touts the PARADIGM-HF Trial Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure | NEJM which found this combination was superior to an ARB alone Joel mentions an early atrial natriuretic peptide trial by Julie Lewis et al. Atrial natriuretic factor in oliguric acute renal failure - American Journal of Kidney Diseases and here's a metanalysis that put this option to bed: Atrial Natriuretic Peptide for Management of Acute Kidney Injury: A Systematic Review and Meta-analysisSnack attack? Check out “Snack induced ANP” Snack-Induced Release of Atrial Natriuretic Factor | NEJMWant more natriuretic peptides than we discussed? Check out this review! Cardiac natriuretic peptides | Nature Reviews Cardiology or this fantastic review: Here's an excellent review of ANP effect on the kidney: ANP-induced signaling cascade and its implications in renal pathophysiologyCerebral salt wasting and elevated brain natriuretic peptide levels after traumatic brain injury: 2 case reportsJoel mentions the study which probed CRIC cohort regarding NSAIDs. Association of Opioids and Nonsteroidal Anti-inflammatory Drugs With Outcomes in CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study - American Journal of Kidney Diseases and you may like the discussion on NephJC: ​​No Pain for the Kidneys from NSAIDs — NephJCThe KDIGO guidelines can be found here CKD-Mineral and Bone Disorder (CKD-MBD) – KDIGO Regulation and Effects of FGF23 in Chronic Kidney DiseaseElegant work on the calcium sensing receptor by Martin Pollak https://doi.org/10.1016/0092-8674(93)90617-YeClaudin 14, PTH, and calcium absorption in the loop of Henle: Parathyroid hormone controls paracellular Ca 2+transport in the thick ascending limb by regulating the tight-junction protein Claudin14Carboxymaltose induced hypophosphatemia by increasing FGF-23. Randomized trial of intravenous iron-induced hypophosphatemiaCurrent "corrected" calcium concept challenged. | The BMJThe Dialysis Encephalopathy Syndrome — Possible Aluminum Intoxication | NEJMNephMadness covered Aluminum binders in 2016.Roger mentioned the use of ferric citrate as a phosphate binder Ferric Citrate Controls Phosphorus and Delivers Iron in Patients on Dialysis | American Society of NephrologyJoel reminded us of the misadventures in efforts to normalize hemoglobin, first in hemodialysis patients The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin | NEJMLater, in patients with CKD, normalization was also not shown to be better: Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease | NEJM , Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia | NEJMA quick shout out for roxadustat and the Nephmadness Anemia region! Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis | NEJM, #NephMadness 2021: Anemia Region – AJKD BlogIn this review of vasopressin, you can find an excellent discussion of basic stimuli and vasopressin receptors: Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems | Physiological ReviewsX-Linked Nephrogenic diabetes insipidus is very rare and there was theory that all patients originated from the same family and traveled to the US on the Hopewell ship JCI - X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. This report describes another family from the Netherlands with nephrogenic DI including the finding that the urine osmolarity never exceeds 200 mOsm/kg. Hereditary Nephrogenic Diabetes Insipidus - GeneReviews® (and here's a family with central diabetes insipidus https://academic.oup.com/jcem/article/81/1/192/2649423?login=true )Although we have all learned that thiazides should be used with diabetes insipidus, to induce mild volume depletion, several case reports and animal data have found that acetazolamide might be the best diuretic for the job. Clinicians from Boston Medical Center tried it out in this report: ​​Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus | NEJM based on exciting data in mice! https://jasn.asnjournals.org/content/27/7/2082.shortADH appears to have an effect on potassium excretion. This was investigated by Giebesch who found, with clearance and micropuncture studies in rats plus isolated perfused tubules, ADH increased potassium secretion Influence of ADH on renal potassium handling: A micropuncture and microperfusion study A corollary should be that inhibition of ADH would increase the risk of hyperkalemia but this was not observed in the SALT-1 and SALT-2 trials. 5% of patients developed hyperkalemia in both the tolvaptan group and the placebo group Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia | NEJMV1 vasopressin as a pressor Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature ReviewWe wondered/debated on our observation that hyponatremia is not reliably seen in patients receiving vasopressin in the ICU. In the VASST trial, Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock, 1 patient in each study arm of nearly 400 patients developed hyponatremia. Note that patients with hyponatremia (

Chapter 6 part 1In this review of vasopressin, you can find an excellent discussion of basic stimuli and vasopressin receptors: Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems | Physiological ReviewsX-Linked Nephrogenic diabetes insipidus is very rare and there was theory that all patients originated from the same family and traveled to the US on the Hopewell ship JCI - X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. This report describes another family from the Netherlands with nephrogenic DI including the finding that the urine osmolarity never exceeds 200 mOsm/kg. Hereditary Nephrogenic Diabetes Insipidus - GeneReviews® (and here's a family with central diabetes insipidus https://academic.oup.com/jcem/article/81/1/192/2649423?login=true )Although we have all learned that thiazides should be used with diabetes insipidus, to induce mild volume depletion, several case reports and animal data have found that acetazolamide might be the best diuretic for the job. Clinicians from Boston Medical Center tried it out in this report: ​​Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus | NEJM based on exciting data in mice! https://jasn.asnjournals.org/content/27/7/2082.shortADH appears to have an effect on potassium excretion. This was investigated by Giebesch who found, with clearance and micropuncture studies in rats plus isolated perfused tubules, ADH increased potassium secretion Influence of ADH on renal potassium handling: A micropuncture and microperfusion study A corollary should be that inhibition of ADH would increase the risk of hyperkalemia but this was not observed in the SALT-1 and SALT-2 trials. 5% of patients developed hyperkalemia in both the tolvaptan group and the placebo group Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia | NEJMV1 vasopressin as a pressor Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature ReviewWe wondered/debated on our observation that hyponatremia is not reliably seen in patients receiving vasopressin in the ICU. In the VASST trial, Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock, 1 patient in each study arm of nearly 400 patients developed hyponatremia. Note that patients with hyponatremia (

References for Chapter 5--the Distal NephronRoger pointed out the fact that the distal nephron can achieve very low urinary sodium as evidenced by observations in people from the Yanomamo tribe Blood pressure and electrolyte excretion in the Yanomamo Indians, an isolated population in this report, 84% of the participants had urinary sodium < 1mmol/24 hours. Information about the Yanomamo Tribe. It looks like they're starting to make chocolate, now! YanomamiThe Yanomami are great observers of natureThe Amazon's Yanomami utterly abandoned by Brazilian authorities: ReportYanomami Amazon reserve invaded by 20,000 miners; Bolsonaro fails to actI believe this is the original study looking at urine sodium and blood pressure in the Yanomamo Indians, but the INTERSALT trial linked above I believe had more robust urine dataThis study mentions the average lipid profile for men and women along with BMI. I didn't mention in the “Voice of God” overview, but there is some interest looking at the Yanomamo and rate of cancer as it relates to the correlation with intracellular potassium to sodium ratiosJosh referred back to his notes and realized that the tightest junctions are in the TOAD not FROG bladders Physiology and Function of the Tight JunctionAn excellent review from McCormick and Ellison on the Distal convoluted tubule in Comprehensive Physiology.We flirt with the disorder of Gordon's syndrome: Familial Hyperkalemic Hypertension | American Society of Nephrology and its alter ego, Gitelman syndrome: Gitelman Syndrome | HypertensionJC spoke about this beautiful report on how calcineurin inhibitors lead to hyperkalemia (and mimic Gordon's syndrome). The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertensionThis superb review of the DCT includes all the highlights of Rose's chapter 5 with a modern lens including “braking” from DCT hypertrophy Distal Convoluted Tubule | American Society of NephrologyEchos of the lessons learned in the DCT can be seen in this review: Diuretic Treatment in Heart Failure | NEJMAnna reminds us of the ALL HAT trial which showed that chlorthalidone was superior to the lisinopril and amlodipine groups (and the alpha blocker dropped out earlier) ​​Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs DiureticNice review of drug induced Hyperuricemia with a deep dive into the mechanisms of diuretic induced Hyperuricemia. Drug-induced hyperuricaemia and goutPlus, despite the concerns that thiazides are weaker than loop diuretics and may not work in CKD, this report suggests that it can still be of use. Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot studyIf you love diuretics, you will love this classic paper from Craig Brater on diuretics Diuretic Therapy | NEJM which also includes the t1/2 of various diuretics and points out that chlorthalidone's half life is 24-55 hours so eliminated after 4-10 days. The hypercalcemia seen in some patients who take thiazides may be the unmasking of primary hyperparathyroidism Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two DecadesAs we discussed the relative importance of DCT vs Proximal tubule for the hypercalcemia seen with thiazides, Amy reminded us of about the TRPV5 knockout mice: JCI - Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 JC mentioned the defect in TRPM6 that can cause severe hypomagnesemia: Novel TRPM6 Mutations in 21 Families with Primary Hypomagnesemia and Secondary HypocalcemiaWe enjoyed talking about Liddle syndrome Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndromeWe wondered about the role of pendrin which was discovered after this book was published. Here's a nice review: The role of pendrin in renal physiology and also a potential therapeutic target for pendrin: Pendrin—A New Target for Diuretic Therapy? | American Society of NephrologyBradykinen Bradykinin B2 receptor antagonist increases chloride and water absorption in rat medullary collecting ductMore Bradykinen Chronic Overexpression of Bradykinin in Kidney Causes Polyuria and Cardiac HypertrophyWe ended on a high note when we considered the urothelium of the American black bear. These magnificent creatures have aquaporins 1 &3 that allow them to reabsorb their own urine during hibernation. The urothelium of a hibernator: the American black bear

Show notes with a full set of references are available here: http://www.rosebook.club/episodes/2021/6/22/chapter-fourAlso, please fill out our listener survey: https://forms.gle/DVdcJikKZkzY56mXA

Chapter Three: How the proximal tubule is like Elizabeth Warren and other truths my friends from Boston taught me References for Chapter 3: Faisy C, Meziani F, PLanquette B et al. Effect of Acetazolamide vs. Placebo on Duration of Invasive Mechanical Ventilation among patients with chronic obstructive pulmonary disease: a randomized clinical trial. JAMA 2016 https://pubmed.ncbi.nlm.nih.gov/26836730/This randomized controlled double blinded multi-center study of acetazolamide to shorten the duration of mechanical ventilation (known as DIABLO) there was no statistically significant difference (though it may have been underpowered to do so).Salazar H, Swanson J, Mozo K, White AC, Cabda MM Acute Mountain sickness impact among travelers to Cusco, Peru J Travel Med 2012 https://pubmed.ncbi.nlm.nih.gov/22776382/ Investigators found that altitude sickness is common and alters travel plans for 1 in 5 travelers but was prescribed infrequently.Buzas GM and Supuran CT. Journal of enzyme inhibition and medicinal chemistry 2015 https://www.tandfonline.com/doi/full/10.3109/14756366.2015.1051042This review describes the use of acetazolamide to treat peptic ulcers and how it was later learned that H. pylori have carbonic anhydrase NORDIC idiopathic intracranial Hypertension Study Writing Committee. The effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA 2014 https://pubmed.ncbi.nlm.nih.gov/24756514/In this multi-centered trial, acetazolamide and low sodium weight reduction diet improved mild visual loss more than diet alone. Mullens W et al. Rationale and design of the ADVOR (acetazolamide in decompensated heart failure with volume overload trial) Eur J Heart Failure 2018 https://pubmed.ncbi.nlm.nih.gov/30238574/This reference explains the rationale for this ongoing trial.Gordon CE, Vantzelfde S and Francis JM. Acetazolamide in Lithium-induced nephrogenic diabetes insipidus NEJM 2016 https://www.nejm.org/doi/full/10.1056/NEJMc1609483A case report of efficacy of acetazolamide in a patient with severe polyuria.Zehnder D et al. Expression of 25-hydroxyvitamin D-1alpha hydroxylase in the human kidney. JASN 1999 This report explores the activity in the enzyme in nephron segments and suggests that the distal nephron may play an important part in the formation of 1,25 vitamin D https://jasn.asnjournals.org/content/10/12/2465Outline: Chapter 3 - This is chapter three, kind of the first real chapter of the book- Proximal Tubule- Reabsorbs 55-60% of the filtrate - Active sodium resorption - 65% of the sodium - 55% of the chloride - 90% of HCO3 - 100% glucose and amino acids - Passive water resorption - Water resorption is isosmotic - Secretion of - Hydrogen - Organic anions - Organic cations - Anatomy - S1, S2, S3 can be differentiated by peptidases - S1 more sodium resorption and hydrogen secretion, high capacity - S2 more organic ion secretion - Cell model - Basolateral membrane - Na-K-ATPase powers all the resorption - Luminal membrane - 100 liters a day crosses the proximal tubule cells - Microvilli to increase surface area - Microvilli has brush border which has carrier proteins as well as carbonic anhydrase - Water permeable, so sodium resorption leads to water resorption - Aquaporin-1 (sounds like this transporter is unique to the proximal tubule and RBC) - HCO3 is reabsorbed early, along with Na, resulting in increased chloride concentration which passively reabsorbed via paracellular route. - Tight junction has only one strand (on freeze fracture) as opposed to 8 in distal nephron - The Na-K-ATPase - Lower activity than in the LOH and distal nephron - Maintained intracellular Na at effective concentration of 30 mmol/L - Interior of the cell is negative due to 3 sodium out and 2 K in, then K leaks back out. - 3 Na out for 2 K in - An ATP sensitive K outflow channel on the basolateral membrane - Increased ATP slows potassium eflux - The idea is if Na-K slows, ATP will accumulate and this will slow K leaving, because there is less potassium entering. - K channel is ATP sensitive, ATP antagonizes K leak. - Highly favorable ELECTROCHEMICAL gradient for sodium to flow into the cell through the luminal membrane - Must be via a channel or carrier - Cotransporters - Amino acids - Phosphate - Glucose - Called secondary active transport - Countertransporters - Only example is H excretion - Basolateral membrane - Na-3HCO3 transporter - Powered by the negative charge in the cell- Chloride resorption - Formate chloride exchanger - Formate combines with hydrogen in the lumen, becomes neutral formic acid, and is reabsorbed where the higher pH causes it to dissociate and recycle again. - Dependent on continued H+ secretion - Chloride moves across basolateral membrane thanks to Cl and KCl transporters, taking advantage of negative intracellular charge- Passive mechanisms of proximal tubule transport - Accounts for one third of fluid resorption - Mechanism - Early proximal tubule resorts most of the bicarb and less of the chloride - Tubular fluid gets a high chloride concentration - Chloride flows through the tight junction down its concentration gradient - Sodium and water follow passively behind - Water moves osmotically into intercellular space from tubular fluid even though the osmolalities are equal since chloride is an ineffective osmole, so tonicity is not the same. ****** - Argues that bicarb is primarily important solute for passive resorbtion - Acetazolamide blocks Na and chloride resorption - Similar thing happens with metabolic acidosis where less bicarb is available to drive passive resorbtion of Na and Cl - Summary - Other than Na-K-ATPase Na-H antiporter main determinant of proximal Na and water resorption - 1. Direct bicarb resorption - Preferential bicarb resorbtion proximally drives passive chloride resorption - Drives active the formate exchanger for chloride resorption- Neurohormonal influence - AT2 drives a lot of Na resorption, primarily in S1 segment - Does not have a net effect on H-CO3 movement - Dopamine antagonizes sodium resorption - Blocks both Na-K-ATPase and - Na H antiporter- Capillary uptake - Starlings. Again - Low hydraulic pressure due to glomerular arteriole - High plasma on oncotic pressure from loss of the filtrate - The two together promote resorption - There maybe movement from interstitial back into tubular fluid (back diffusion) conflicting data- Glomerular tubular balance - The fractional tubular reabsorption remains constant despite changes in GFR (tubular load) - It is essential the GFR is matched by resorption - The rise in capillary osmotic pressure with increased GFR via increased filtration fraction is one mechanism of GT balance - Glomerular tubular balance os one of three mechanisms that prevents fluid delivery from exceeding the resorptive capacity of the tubules - GT balance - TG feedback - Autoregulation - GT balance can be altered if patients are volume overloaded or depleted - Closes this section with a story of a kid born without a brush border - Primacy of sodium in proximal tubule activity - Discusses bicarb resorbtion - There is no Tm for Bicarb as long as volume overload is prevented, in rats can rise over 60! - If you give NaHCO3 you get volume overload and the Tm I about 60 - Glucose - S1 and S2 have high capacity, low affinity glucose resorption - S3 has high affinity 2 Na fo every glucose - Tm glucose is 375 mg/min - For a GFR of 125t that comes out to 300mg/dL - 125 ml/min * 3mg/ml (300 mg/dL) = 375 mg/min - Functionally this is 200 mg/dL due to splay - Urea - Only 50-60 of filtered urea is excreted - Calcium Loop and distal tubule - Phosphate - 3Na-Phosphate high affinity transporters late in proximal tubule - three types of Na-Phos transporters, type 2 are the most important - regulated by PTH and plasma phosphate - PTH suppresses Phos resorption -Metabolic acidosis also reduces phosphate resorption (good to have phosphate in the tubule to soak up H+ - Decreased tubular pH converts HPO42- to H2PO4- which has lower affinity for phosphate binding site - Mg Loop and distal tubule - Uric AcidWhy do I love acetazolamide?- I love the proximal tubule- Many uses- Often forgottenMOA- Inhibit carbonic anhydraseMain effects- Renal: less bicarb reabsorption (ie less H secretion) à more distal Na/bicarb delivery à hypokalemic metabolic acidosis- Brain: reduce CSF production, reduce ICP/IOP, aqueous humor- Pulm: COPDNotes- Tolerance develops in 2-3 days- Sulfonamide derivative- Highly protein bound, eliminated by kidneys Source: Buzas and upuran, JEIMC, 2016S Data:1968 - High altitudeHigh altitude usually results in respiratory alkalosisAcetazolamide – lessens symptoms of altitude sickness (insomnia, headache) which occur because of periodic breathing/apnea1979- NEJM study took 9 mountaineers asleep at 5360 meters à improvement in sleep, improved SaO2 from 72 to 78.7 mmHg, reduce periodic breathing, increased alveolar ventilation (pCO2 change from 37 mmHg to 30.8mm Hg)1950s - Seizures/migrainesCAI reduces pH (more H intracellularly), K movement extracellularly à hyperpolarization and increase in seizure thresholdWeak CAI (Topamax, zonisamide) but not though to be important mechanism of antiseizure effect (topamax enhances inhibitory effect of GABA, block voltage dependent Na and Ca channels)Pulmonary/COPDThought to help with the metabolic alkalosis and as a respiratory stimulant to increase RR, TV, reduce ventilator timeIn 2001 Cochrane review – no difference in clinical outcomes, but did reduce pH and bicarb minimallyDIABLO study (RCT) on ventilated COPD patients – no difference in median duration of mechanical ventilation despite correction of metabolic alkalosisHigh altitude erythropoiesis (Monge disease)First described in 1925 via Dr. Carlos Monge Medrano (Peruvian doctor), seen in people living > 2500-3000 meters (more common in South America than other high altitude areas)Usually chronic altitude sickness with HgB > 21 g/dL + chronic hypoxemia, pHTNAcetazolamide – reduces polycythemia because induces a met acidosis à increases ventilation and arterial PPO2 and SaO2 à blunts erythropoiesis and reduces HCT and improves pulmonary vascular resistanceGI ulcersWhen H2 and PPI available, less useHistory: 1932 – observed alkaline tide, presumed existence of gastric CA (demonstrated in 1939)Acetazolamide was used to inhibit acid secretion in 1960s, ulcer symptoms, with reversible metabolic acidosis, BUT lots of SE (electrolyte losses, used Na/K/Mg salts to help, renal colic, headache, fatigue, etc)Later found H. Pylori encodes for two different CasHelps to acclimatize to acidic environmentBasically, the Ca changes CO2 into H+ and HCO3They also have a urease which produces NH3The NH3 binds with H+, leaving an alkaline environment for them to live inInhibition of CA with acetazolamide is lethal for pathogen in vitro1940sFound there was CA in pancreasThought acetazolamide to reduce volume of secretions from NGT (output from exocrine pancreas) Source: Human Anatomy at Colby Blog Diuretic resistanceIf develop hyperchloremic metabolic alkalosis, short course of acetazolamide + spironolactone (b/c need distal Na blockage) à can helpMay help with urine alkalization (ie uric acid stone) but increases risk of calcium phosphate stonesADVOR trial acetazolamide in HF exacerbation in Belgiumuse may help to prevent new episode, lower total diuretic doseCSF reduction (pseudotumor cerebri)Reduces CSF by as much as 48% when > 99.5% of CA in choroid plexus is inhibitedNORDIC trial (acetazolamide v. placebo) – improvement in visual symptoms especially if advanced papilledema, and reduced opening pressure)Side note also used off label to help with increased ICP and CSF leaks, as alternative to VP shunts, repeat LPs, etc Source: Eftekari et al, Fluid Barriers CNS, 2019.

The exciting conclusion to Chapter Two: Renal Circulation and Glomerular Filtration Rate - Determinants of GFR - First step in making urine is separation of an ultrafiltrate - Governed by starling forces - Balance of hydraulic and osmotic forces - GFR = LpS (P gc – P us - Osmotic Pressure Cap p) - Normal GFR 95 in women, 120 in men - Cap Hydrolic pressure remains constant - glom cap Oncotic progressively rises - Due to filtration of protein free fluid (protein concentration rises in the capillary) - Filtration gradient begins at 13 mmHg and falls to zero after filtration of 20% or RPF! - GFR is capped at 20% of RPF called filtration equilibrium - So GFR is dependent on RPF, unless you can change glomerular hydraulic pressure - Glomerular hydraulic pressure is controlled by balance of twin arteriole (afferent and efferent) - Constriction of afferent arteriole reduces RPF, GFR, and glom pressure - Dilation of afferent arteriole increases RPF, GFR, and glom pressure - Constriction of the efferent arteriole increases Glom pressure, increasing GFR - Besides glom hydrostatic pressure the other starlings forces are rarely relevant to changes in GFRLetty says: referred to this NEJM review article later JC thought she was referring to something else -see #2- and then Roger referred to this again)Normotensive Acute Renal Failure from Gary Abuelo in NEJM 2007. https://www.nejm.org/doi/10.1056/NEJMra064398 (note in this article, Dr. Abuelo acknowledges the newer terminology of the time, AKI rather than ARF but chooses not to embrace it). In figure 2, he highlights the classic examples of how autoregulation can be affected. In the table, additional examples are provided but all within the framework of alterations related to autoregulation and the interplay between the two resistance vessels.- Regulation of GFR - Autoregulation - The ability to keep glomerular pressure constant over wide range of systemic arterial pressure - When pressure < 70 autoregulation fails and GFR will fall with decreases in systemic pressure - When pressure falls below 40-50 GFR ceases - At least some of this autoregulation is mediated with Ang2. Giving ACEi markedly disrupts autoregulation - Nitric oxide, not important - TGF - Chloride in macula densa - Blocked by furosemide - Group affect of nephrons - Ang 2 sensitizes - Adenosine mediates - Function of TGF - 90% of filtrate is reabsobed in PT and LOH - 10% is reabsobed dismally - Need to control the amount of fluid delivered distally to prevent overwhelming the resorptive capacity of the distal nephron - Talks about acute renal success without naming it (but did reference it) - Mentions glucosuria blunts TGF. Hmmm... - Neurohormonal influences - Volume changes in ang2, sympathetic NS - Role of PGE - Interesting discussion of change of the nephrons perfumed with volume depletion, shifting of blood from outer coretex to inner medullary cortical gloms with their long loops - Dopamine and ANP both increased with volume up - Dopamine causes vasodilation of afferent and efferent arteriole - ANP causes afferent vasodilation and efferent vasodilation constriction, increasing GFR without affecting RPF - Glomerular hemodynamics and renal failure - Decreased glomerular mass results in hyperfiltration of remaining gloms - Mediated through afferent vasodilationJC talks about this classic study in critical care: High vs. Low blood pressure target in Septic Shock. https://www.nejm.org/doi/pdf/10.1056/NEJMoa1312173In this multi-center open label trial of 776 patients randomized to either a MAP of 65-70 or 80-85 with the primary endpoint of mortality. There was no difference in mortality at 28 days between the two groups (but a small difference in AKI in the patients who had chronic HTN- in the higher BP target, there was a decrease in need for RRT; there was also a higher incidence of afib in the high target group overall). - Results in compensation and stable GFR in short term, long term maladaptive - Reason for ACEi- Clinical Evaluation of Renal Circulation - Concept of clearance and measurement of GFR - GFR as an index of functioning renal mass - Had a patient today s/p nephrotomy, 72 years old, Cr0.9!Melanie referred to this article in Circulation which demonstrates that SGLT2 inhibitors do decrease single nephron GFR (in mice) and that this is related to a decrease in the afferent arteriole diameter and then they show that this is related to a local increase in adenosine. Kidokoro K, Cherney DZI et al. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging Circulation 140 (4) 2019https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.037418 - Fall in GFR earlier and only sign of renal disease - Serial monitoring is used to assess severity and follow the course of disease - GFR is useful for dosing drugs - How to measure GFR - Consider fructose polysaccharide inulin (love the parenthetical, not insulin) - Inulin filtered = inulin excreted - Filtered inulin = plasma inulin concentration x GFR - Inulin excreted = urine concentration x urine volume - Use Alber a to get GFR = [Urine]insulin x urine volume / [plasma]inulin - GFR = inulin clearance - There is not an available assay for inulin - Creatinine clearance - Freely filtered - Not reanbsorbed - Not metabolized - Small amount excreted - CrCl exceeds GFR by 10-20%Roger says the SGLT2 inhibitor story is about the afferent arteriole and he thought it reminded him of the MDRD study and the concept that the lower protein intake would be protective and delay the progression of CKD. The concept was that low protein diets would decrease glomerular pressure by decreasing the intake of amino acids that lead to arteriolar vasodilation and increased GFR. Klaur S, Levey AS et al. The effects of Dietary Protein Restirciton and blood-pressure control on the progression of chronic renal disease. NEJM 1994 330:877-884. https://www.nejm.org/doi/full/10.1056/nejm199403313301301 - Compensated for by noncreatinine chromogens (acetone proteins, as Orbi acid, pyruvate) that over estimate Cr by 10-20% - Cr Cl = [Urine]cr x urine volume / [Plasma]cr - Two major limitations - Incomplete collections - 20-25 mg/kg in adult men - 15-20 mg/kg in adult womenThe term “Acute renal success” comes from Thurau K and Boylan JW. Acute renal success. The unexpected logic of oliguria in acute renal failure. Am J Med 1976 61(3): 3038-15. - Falls by 50% from age 50 to 90 to 10 mg/kg - Increased tubular secretion with decreased kidney function - GFR of 40-80 cr secretion may account for as much as 35% of creatinine excretion - In some cases CrCl can exceed GFR by a factor of 2 - Give cimetidine 1200 mg! - It is important to appreciate however that exact knowledge of GFR is not required. More important to know if GFR is changing - Why is radio labeling the solution DTPA and iothalamate? - Talks about the reality of progressive disease despite stable GFR and CrCl - On to plasma Cr and GFRIf you think placing dialysis lines is too easy, here is a wonderful review of micropuncture technique in the kidneys by Volker Vallon.Micropuncturing the Nephron. Pflugers Arch 2009 458(1): 189-201. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954491/ - Creatinine excretion = creatinine production (and this is constant) - Creatinine excretion = [Cr] x GFR = constant - If GFR falls in half, creatinine excretion will fall in half, while creatinine production remains the same, so creatinine will rise and rise until [Cr] x GFR = creatinine production and then it will level off. - Changes in creatinine load - High protein diet can increase it - Vegetarian diet can decrease itJC brought up studies on fenoldopam, of which there are many. This is one such study in patients undergoing cardiac surgery. JAMA 2014 Bove T et al. Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial https://pubmed.ncbi.nlm.nih.gov/25265449/ - Cooked meat can increase Cr by 1 mg/dL - Talks about need for steady state to assess GFR - Talks about the curvilinear relationship - Then he talks Cockcroft GaultThe one, the only: The Cockcroft Gault: Prediction of creatinine clearance from serum creatinine. Nephron 16: 31–41, 1976 https://pubmed.ncbi.nlm.nih.gov/1244564/ - Cirrhosis masks kidney insufficiency, low meat intake, low BUN production - Can someone explain what we are supposed to take from figure 2-12 - Stable Cr does not mean stable kidney diseaseRoger describes the study design for the seminal paper on the use of ACE inhibitors to slow the decline in renal function in diabetic kidney disease (then called diabetic nephropathy) and the decision to use the doubling of the serum creatinine as an endpoint. Lewis EJ The effect of Angiotensin-converting-enzyme inhibition on diabetic nephropathy NEJM 1993 https://www.nejm.org/doi/full/10.1056/NEJM199311113292004 - Ketoacidosis can raise the Cr 0.5 to 2.0mg/dL - On to BUN - Destination of amino acids produces ammonia - We detoxify ammonia by converting to urea - Increased with increased protein load - Increased catabolismMelanie mentioned an old study on ingestion of expired blood: Cohen TD. Induced azotemia in humans following massive protein and blood ingestion and the mechanism of azotemia in gastrointestinal hemorrhage. AM J Med Sci 1956 https://pubmed.ncbi.nlm.nih.gov/13302213/ - Tetracycline causes decreased anabolism - Trauma - Steroids - Urea excretion is variable and tied to hydration and FF - Renal plasma flow and PAH

Back by popular demand…all two of you…the second chapter of The Clinical Physiology of Acid Base and Electrolyte Disorders. Chapter Outline- Renal Circulation and GFR - RBF is 20% of cardiac output - In terms of mL per 100 g organ weight it is 4x the liver and exercising muscle and 8x coronary blood flow! - After the glomeruli the efferent arteriole have two fates - Peritubular capillaries in the cortex - Peritubular capillaries are not necessarily associated with their parent glomeruli. Weird. - Vasa recta from juxtamedullary glomeruli in the medullaJoel Says: This seems wrong. Solute balance can be maintained down to a very low GFR. The R^2 here would be very low. Prove me wrong. - States that GFR is an important determinant of solute and water excretion. - Glomerular anatomy and function - Structure Four editions of the Bud Bible up top and a copy of Bud Light on the bottom. - Glomerulus is a tuft of capillaries - Enclosed in a capsule of epithelial cells, called Bowman's capsule - The epithelial cells of Bowman's capsule are continuous with the epithelial cells of the proximal tubule Looking at scanning EMs of the glomerulus is one of life's simple pleasures—Josh. Josh says: Look at the review in Nature Reviews Nephrology from Rachel Lennon's groupComplexities of the glomerular basement membrane - Filtration barrier - Epithelial cell (podocyte) - Epithelial cells adhere to the basement membrane via foot processes and the foot processes have slit diaphragms - Basement membrane New Super-resolution structure of the GBM: https://elifesciences.org/articles/01149 Hi res microscopy is really hi-res. Technique is call ed STORM. Melanie talks about conduits through the glomeruli. Here is a cool review: Why until just now? Undiscovered uniqueness of the human glomerulus! by L. Gabriel Navar, Owen RichfieldAm J Physiol Renal Physiol. 2018 Nov 1; 315(5): F1345–F1346. Published online 2018 Aug 15. doi: 10.1152/ajprenal.00369.2018 PMCID: PMC6293291 - Produced by both the endothelial cells and podocytes - Formed from type IV collagen - Abnormalities of type 4 collagen cause Alport - The gene coding for the alpha 5 chain is the culprit - COL4A5 - Abnormal Alpha 3 and 4 chains can also cause hereditary nephritis - Has other substances - Laminin - Nidogen - Heparin sulfate proteoglycans - Provides the negative charge - Enthothelial cell (fenestrated) - Protein excretion - Glomerular function: allow filtration of small solutes (Na and urea) while preventing filtration of larger molecules - Insulin MW 5,200 is freely filtered (upper range of freely filtered) - Preventing loss of protein prevents - Negative nitrogen balance - Development of hypoalbuminemia - Infection from loss of immunoglobulin - Size and charge selectivity of the GBM - pores are between cords of type 4 collagen - The epithelial cells and slit diaphragms matter - Macromolecules that pass through GBM can accumulate underneath the epithelial layer - Isolated GBM in invitro studies is much more permeable to than intact glomerulus - There is increased protein filtration in areas where the epithelial cells have detached from the GBM Josh really likes this figure from another Nature Reviews Nephrology paper. This one by Moeller and Chia-Gil. - Mutations in nephrin, localized to the slit diaphragm causes congenital nephrotic syndrome - Charge selectivity is important - Neutral and cationic particle are more likely to be filtered - Albumin (negative charge) is filtered 5% as well as same size neutral dextrans - In glomerular disease, while there is increased filtration of proteins there is decreased filtration of small solutes due to loss of glomerular surface areaJC says: Take a look at this research on the serving coefficient in glomerular disease. Some surprising results.Glomerular dysfunction in nephrotic humans with minimal changes or focal glomerulosclerosis - Why do people in remission have what appears to be spilling more high molecular radius particles than normal and why do patients with active MCD have lower clearance across all molecular diameters? - Other glomerular functionsJosh says: Take a look at this interesting paper by Butt et alA molecular mechanism explaining albuminuria in kidney disease - Synthetic - Epithelial cells produce GBM - Phagocytic - Remove circulating macromolecules that pass through GBM and get trapped in subepithelial spaceJosh says: The sFLT1 (soluble VEGF receptor) relationship to preeclampsia is just so cool. And here's the paper:Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsiaAnd in the NEJM: VEGF Inhibition and Renal Thrombotic Microangiopathy - Endocrine - Enthothelial cells regulate vascular tone by releasing - Prostacyclin - Endothelin - Nitric oxideJC says: Do yourself a favor and spend some time learning about extraglomerular mesangial cells with Stuart Shankland Extraglomerular origin of the mesangial cell after injury. A new role of the juxtaglomerular apparatusJoel adds, if you ever get a chance to party with Dr. Shankland, don't skip out. - Mesangial cells, two types - Intrinsic Mesangial cell - Microfilaments similar to smooth muscle - Responds to Ang2 - Regulates glomerular hemodynamics - Can release cytokines - Can respond to cytokines by proliferation - Circulating macrophages and monocytes - Phagocytic function - Clear molecules that get through the endothelial wall but cant get through the GBMJosh says, “Topf, get it right. Its Ree-nin not renin. Classic letter to JAMA. - Renin-Angiotensin System - Afferent arteriole contain specialized cells called juxtaglomerular cells - Produce prorenin which cleaved into renin - Stimuli for renin release - Hypotension - Volume depletion - Increased sympathetic activity - Renin catalyze the production of ang1 from angiotensinogen - Ang1 is catalyze to Ang2 by ACE located in the - Lung - Endothelial cells - Glomeruli itself pic.twitter.com/DaDfS7u8se— Roger Rodby (@NephRodby) February 22, 2021 - Discussion of local renin and Aniotensinogen - Explains why ACEi are useful even with low systemic renin levels and Ang2 - Actions of Ang2 - Sodium and water retention - By direct Na reabsorption in the early PT (and in the proximal tubule, water is permeable to the epithelium so every sodium reabsobed, brings a water molecule along for the osmotic ride. - Stimulates the Na-H antiporter - 40-50% of Na reabsorption in the S1 segment of the PT is due to Ang2 - By stimulation of aldosterone - Ang2 that stimulates Aldo comes from the kidney and from the adrenal gland itself - VasoconstrictionJosh talks angiotensin:Tenses the angios--love this Melanie!1961 paper from del Greco (who's endowed chair Dan Batlle has now) trying AT2 in "hopeless" patients and dialysis patients:https://jamanetwork.com/journals/jama/article-abstract/332265Great EM-crit/pulmcrit discussion here:https://emcrit.org/emcrit/deeper-vasopressors-athos-3/and caveats here:https://emcrit.org/pulmcrit/angiotensin-ii/ - Arteriolar vasoconstriction - Ang2 important for raising BP in RAS - Ang2 important in maintaining BP with volume depletion or in CHF, liver disease - Giving ACEi to cirrhosis can cause BP to dump 25 points - Regulation of GFR - Affects constriction at afferent arteriole and efferent arteriole - Mediated via thromboxane JC talks about the ATHOS trial and how there is a signal for improved outcomes especially in patients requiring renal replacement therapy.Angiotensin II for the Treatment of Vasodilatory ShockOutcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II - Afferent arteriole starts bigger so reductions have less of an effect than constriction does on the narrower efferent arteriole. - This results in a fall of RBF due to increased resistance but maintaining GFR by increasing inrtaglomerular pressure. - Also stimulates prostaglandins which are vasodilator, modulating this affectJoel says: You haven't heard of the Trolly Problem? Oh you need to take 5 minutes and read this. - It can stimulate contraction of the mesangium reducing surface area of the glom reducing filtration. - It sensitizes the afferent arteriole to TG feedback so it can reduce glomerular flow in response to increased chloride detection in the TLoH. - Control of renin secretionEver wanted to know about intrarenal renin concentrations? Yeah, me neither. But JC's got you covered: Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. - Primarily sodium intake, increased intake results in less renin - Mediated by baroreceptors - Baroreceptors in afferent vessel wall - Cardiac and arterial baroreceptors which activate the sympathetic nervous system and catecholamines which then stimulates reninRoger says: Do your self a favor and read about Yanomamo IndiansBlood pressure and electrolyte excretion in the Yanomamo Indians, an isolated population - Cells of the macula densa in the early distal tubule which detect decreased chloride delivery - This allows loop diuretics to be particularly effective at increasing renin as they block chloride resorption - Suppression of renin in response to chloride is mediated by adenosine - Stimulation of renin in response to decreased chloride is mediated by PGE - The PGE cause local vasodilation so the kidney maintained a rich blood flow while using renin and Ang2 to cause systemic vasoconstrictionAnna's notes for the deep dive in glomerular barrierOur understanding is based on technology available at the time. Even in 1920s, there was thought that tubular reuptake of protein may be important, but studies never demonstrated this til 2007 and even then are debated. 2007 Russo, et al (and BM at IU!) showed that The normal kidney filters nephrotic levels of albumin and that failure of retrieval by proximal tubule cells is what separates proteinuria from nonproteinuria. This was countered by a study in 2009 demonstrating much lower GSC and suggesting that the high GSC in the 2007 could be the result of nonphysiologic states.Check out this 2008 debate in JASN regarding the validity of the charge model and “normal” albumin in the glomerular filtrate. Hotly debated with too many studies to cite. 2017: Lawrence et al publish their findings that the GBM and podocyte processes are sufficient and the slit diaphragm likely does not exist. They used labeled proteins and confocal microscopy to determine migration of particles through the enodthelium and GBM. They also injected NaSCN oligoclusters from the size of albumin (66kDa)up to the size of IgG dimers (300 kDa) into mice, then fixed. The size-sensitive permeation into the lamina densa of the GBM and the podocyte glycocalyx of albumin and uptake of any “escaping” albumin by the proximal tubule was also observed. This countered the common prior conception that the slit diaphragms pores are the site of albumin “capture.” For your reading pleasure the review of Clinical Physiology of Acid-Base and Electrolyte Disorders Fourth Edition in Annals of Internal Medicine

The Channel Gang discusses the name of their new podcast and then discuss chapter one of The Book.